奥地利专利AT516070A1 Process for the preparation of polyguanidines

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专利摘要:
The invention relates to a process for the preparation of polycondensation products of guanidine, aminoguanidine or diaminoguanidine G with one or more benzylic dihalides BDH according to the following reaction scheme: wherein each X is a halogen, preferably chlorine or bromine; R 1 represents an aromatic ring system having at least one aromatic ring optionally containing one or more heteroatoms selected from O, N and S; Gua is a guanidinediyl, aminoguanidinediyl or diaminoguanidinediyl radical; Y stands for H-Gua and Z stands for H; or Y and Z together represent a chemical bond to give a cyclic structure; wherein at least one benzylic dihalide BDH is subjected to a polycondensation reaction with an excess of guanidine, aminoguanidine or diamineguanidine G with elimination of HX.
公开号:AT516070A1
申请号:T609/2014
申请日:2014-07-31
公开日:2016-02-15
发明作者:
申请人:Sealife Pharma Gmbh；
IPC主号:

专利说明:

The present invention relates to a novel process for the preparation of poly-guanidines, polycondensation products prepared in this way and their use as antimicrobial agents.
STATE OF THE ART
Polyguanidines of the general formula below as well as various derivatives thereof have long been known.
In the patent literature already in 1943 in US Patent 2,325,586 several manufacturing processes of various polyguanidines by polycondensation of i) guanidine or salts thereof, ii) cyanogen halides, iii) dicyanamides or iv) Isocyaniddihalo-genides with diamines or v) of two dicyandiamides with each other (which Cyano-substituted polyguanidines results), as well as the use of the polyguanidines thus produced described as Därbehilfsmittel:
As diamines in reactions i) to iv), both alkylene and phenylenediamines as well as oxyalkylene or polyetherdiamines, as should also be known as Jeffamine®, were disclosed at that time.
Decades later, such polyguanidines have also proved to be excellent biocides. Thus, a group to Oskar Schmidt in WO 99/54291 A1 discloses the production of microbicidal Polyhexamethylenguanidinen, in WO 01/85676 A1 biocidal polyguanidines, which are prepared by condensation of guanidine with polyoxyalkylenes, and in WO 2006/047800 A1 as biocides, especially as Fungicidal polyguanidine derivatives formed by polycondensation of guanidine with a mixture of alkylenediamine and oxyalkylenediamine intended to have lower toxicity than polymers containing only one of the two types of divalent Ri.
WO 02/30877 A1 describes similar polyguanidines as disinfectants, which additionally contain phenylene groups in the chains. A Russian research group (Tets, Tets and Krasnov) discloses in WO 2011/043690 A1, US 2011/0269936 A1 and EP 2,520,605 A1 derived biocidal polyguanidines of the following formula, by polycondensation of guanidine and hexamethylenediamine in the presence of Hydrazine hydrate are prepared:
Thus, during the polycondensation, the hydrazine replaces-at least formally-an amino group of either only one or two guanidine groups, thereby obtaining block copolymers in which poly (hexamethylene-guanidine) blocks alternate with poly (hexamethyleneaminoguanidine) blocks and the two types of blocks are each linked together via guanidine dimers, as shown below:
These polymers and acid addition salts thereof are also intended to act as biocides against bacteria, viruses and fungi. However, in the examples of these applications in which 7 different polymers were prepared, except that of Example 1, a " solid, nearly colorless, transparent substance " was, no physical data on the products obtained.
With regard to the possible structures which may arise during the polycondensations of guanidinium with diamines, there are several articles of a research group of Graz University of Technology, e.g. Albert et al., Biomacromolecules 4 (6), 1811-1817 (2003), and Public et al., Macromol. Rap. Comm. 24 (9), 567-570 (2003). In addition to the various possibilities of terminating the linear polymer chains with one of the starting monomers in each case usually form in a non-negligible proportion, the u.a. depends on the chain length of the diamine, also cyclic molecules of the following general formula:
The main disadvantages of virtually all of the polyguanidine derivatives described above are, on the one hand, the not negligible toxicity of these products and, in the case of the use of highly reactive components, relatively complex production processes, and also the use of toxicologically known components such as hydrazine, Therefore, the present inventors have begun to research solutions.
In the course of their research, the inventors had found that polycondensation products of amino and diaminoguanidine with amines surprisingly 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 antimicrobials.
These results are disclosed in pending patent applications AT A 53/2013 and PCT / AT2014 / 050026 which claim polyguanidine derivatives of the formula below and salts thereof:
wherein X is selected from -NH 2, aminoguanidino and 1,3-diaminoguanidino; Y is selected from -H and -R1-NH2; or X and Y together represent a chemical bond to give a cyclic structure;
Ri is selected from divalent organic radicals having from 2 to 20 carbon atoms in which one or more carbon atoms are optionally replaced by O or N; a and b are each 0 or 1, where a + b * 2 when no 1,3-diamino-guanidine units are included; R2 is selected from -H and -NH2 where R2 is -NH2 when a + b = 0, R2 is -H or -NH2 when a + b is 1 and R2 is -H when a + b = 2 is; and n > 2 is.
As a method for preparing these new poly (di) aminoguanidines, analogous diamines with amino and / or diaminoguanidine were polycondensed by heating in analogy to the then known prior art.
Without wishing to be bound by theory, the inventors believe that amino and diaminoguanidino moieties (collectively referred to as " aminoguanidione " unless otherwise specified in the context) are more compatible with human eukaryotic cells than guanidino And in particular as those polymers containing the hydrazine-bridged guanidine dimers shown above.
However, some of these new aminoguanidine compounds with respect to antimicrobial efficacy or toxicity have not been found to be completely satisfactory, and the manufacturing process is also in need of improvement, as it requires very high temperatures for the melt polymerization and still continue to use a certain diamines problematic residual monomer content brings with it.
The aim of the present invention was therefore to provide further polyguanidine derivatives having even better properties and an advantageous production method therefor.
DISCLOSURE OF THE INVENTION
This object is achieved in a first aspect of the invention by providing a process for the preparation of polycondensation products of guanidine, amino-guanidine or diaminoguanidine G with one or more benzylic dihaiongeneic BDHs according to the following reaction scheme:
wherein each X is a halogen, preferably chlorine or bromine;
Ri is an aromatic ring system having at least one aromatic ring optionally containing one or more heteroatoms selected from Ο, N and S;
Gua represents a guanidine diyl, aminoguanidine diyl or diaminoguanidine diyl residue; Y stands for H-Gua and Z stands for H; or Y and Ζ together represent a chemical bond to give a cyclic structure; wherein at least one benzylic dihalide BDH is subjected to a polycondensation reaction with an excess of guanidine, aminoguanidine or diaminoguanidine G with elimination of HX to form a polyguanidine of the following formula (I), (II) or (III):
or with a cyclic structure obtained by ring closure with elimination of a corresponding guanidine, or to give a salt of the polyguanidine.
In this production process, in contrast to the prior art, the polycondensation is not carried out with elimination of ammonia, but of hydrogen halide, e.g. HCl or HBr, which forms acid addition salts with the amino or imino groups in the molecule, thereby obviating the use of an acid scavenger.
This also has the consequence that the polycondensation does not necessarily have to be carried out in the melt, although for reasons of process economy and in accordance with the present invention, melt polymerization is the preferred reaction regime. Therefore, in preferred embodiments, the at least one benzylic dihalide BDH is reacted with guanidine, aminoguanidine or diaminoguanidine-din G by heating the reactants to a temperature above their melting temperatures, preferably the polymerization reaction over a period of at least 2 hours, more preferably at least 3 hours. is carried out. In particular, the reaction is carried out in two stages at different temperatures, a first, lower and a second, higher temperature, in analogy to the inventors' previous method, in order to ensure as complete a conversion as possible and thereby larger chain lengths with simultaneously reduced residual monomer content. Quite surprisingly, however, the inventors have found that when using benzylic structures, as in the prior art, mixtures of polycondensation products of different structures are formed. However, the main products do not correspond to the structures known in the earlier applications of the inventors with only singly substituted nitrogen, but already singly substituted nitrogen apparently reacts a second time to give the above structures of formulas (I) to (III).
Without wishing to be bound by theory, the inventors believe that this is due to a better stabilization of the transition state during nucleophilic substitution on the benzylic methylene group, so that it is further believed that similar to at least a majority of the known benzylic Structures will be established, ie in structures with an electronically-promoted methylene group attached to an aromatic ring. For this reason, any further substituents on these aromatic rings should not be specifically limited at present, as long as the aromaticity of the respective ring is not abolished or the ring electron density is significantly reduced.
In these structures of formulas (I) to (III), the remainder of the guanidine or amino guanidine molecule, except for the double-chain nitrogen atom, protrudes from the chain, making it more accessible for further reactions. Depending on the guanidine used, i. Although guanidine itself, aminoguanidine or diamino-guanidine, varies the percentage of the particular product of formula (I), (II) or (III), it represents the majority formed product in all three cases, even in the case of unsubstituted guanidine , which was the most surprising given the strongest resonance stabilization of the binding electrons among the three guanidine derivatives.
For example, in the polyaminoguanidine of Example 1, an HMBC cross-peak of the respective in-chain benzylic CH 2 protons (apparently an AB system at 3.8 and 4.2.) Was determined by HMBC NMR ppm) to the respective in-chain benzylic carbon atoms (at 64 ppm). As a minor component (~ 15% by 1 H NMR), signals indicative of alkylation of guanidine nitrogen (AB system at 4.3 and 4.5 ppm, HMBC cross peaks in the guanidine carbon region at 160 ppm) were found to be Basic condition for a chain branching. As an additional minor component, a signal at 8.08 ppm indicates a benzylic imine functionality (malt oxidation type).
In this new type of structure, the inventors expected even better antimicrobial activity than their earlier polyaminoguanidines, which could also be confirmed, as demonstrated by the following embodiments of the invention: biocide activity is markedly increased while at the same time the toxicity is somewhat lower ,
The latter, the inventors assume, without wishing to be bound by theory, may be due, inter alia, to the higher average chain lengths compared to the earlier polyaminoguanidines and the still lower residual monomer content.
To optimize the reaction conditions in order to find the best possible compromise between reaction time, chain length and residual monomer content, the inventors have carried out experimental series with different ratios between the benzylic dihalide BDH and the guanidines G, different temperatures and different reaction times and found that in a Ratio BDH / G just below 2, the products thus obtained have given the best biological results, the reaction mixtures preferably first for 2 to 3 hours at a temperature of about 150-170 ° C and then for 1 to 2 hours to a temperature of 180 -190 ° C should be heated.
In a second aspect of the invention, there are provided by the present invention novel polyguanidines corresponding to the following formulas (I) to (III), namely a polyguanidine corresponding to the following formula (I):
or having a cyclic structure obtained by ring closure with the elimination of a guanidine; a polyguanidine corresponding to the following formula (II):
or having a cyclic structure obtained by ring closure with the elimination of an aminoguanidine, and a polyguanidine corresponding to the following formula (III):
or having a cyclic structure obtained by ring closure with the elimination of a diaminoguanidine; wherein each Ri is an aromatic ring system having at least one aromatic ring optionally containing one or more heteroatoms selected from Ο, N and S, in preferred embodiments of divalent radicals of optionally substituted benzene, furan, pyrrole, thiophene, pyridine and biphenyl , More preferably from divalent radicals of benzene, biphenyl and fluorene, which have already given good results.
Due to the high antimicrobial efficacy of the novel structures, in a third aspect, the invention provides a novel polyguanidine as defined above for use as an antibiotic, preferably for combating bacterial infections in a human or animal patient. The polyguanidine may serve for topical or systemic administration, preferably for administration in the form of a drug or a pharmaceutical composition.
Alternatively, however, the novel polyguanidines may also be used as antimicrobial agents ex vivo, preferably as the active component of antimicrobial paints, coatings, films or membranes or the like.
Accordingly, in a fourth aspect, the invention provides a pharmaceutical or pharmaceutical composition for controlling bacterial infections in a human or animal patient comprising at least one of the novel polyguanidines as an antibiotic, and preferably further comprising at least one pharmaceutically acceptable carrier or excipient and optionally or more adjuvants and / or one or more other active ingredients.
Preferably, the drug or pharmaceutical composition comprises at least one other active ingredient which also has antimicrobial activity to enhance the effect and to take advantage of any synergistic effects. The at least one other active ingredient may sometimes also be active against a condition other than a bacterial infection. Only as examples are mentioned antidiarrheals and so-called gastric saver.
The invention will be further described by way of non-limiting examples. EXAMPLES Example 1
Preparation of Polvaminoquanidine (1)
α, α'-Dhlchloro-p-xylene (880 mg, 5.03 mmol) and 1.95 equivalents of aminoguanidine hydrochloride (1083 mg, 9.80 mmol) were heated to 160 in an open reaction vessel with stirring for 3 h ° C, then heated to 180 ° C for 2 h. After cooling the reaction mixture below 80 ° C, about ten times the amount of water was added to the reaction product, and after thorough mixing by stirring or sonication, a clear, slightly yellowish solution was obtained. This was filtered through a 0.2 μm PTFE membrane and then evaporated to give polyguanidine (1) as a yellowish, amorphous solid.
For analysis, a sample was dissolved in ten times the amount of D20. When 1H and 13C NMR spectra were recorded, DSS (4,4-dimethyl-4-silapentane-1-sulfonic acid) was added as an internal standard for referencing: 1H-NMR (D20), δ (ppm): 3 , 72-3.91 (ad, CH2 -NfGuaJ-CH; *, Yes, b = 12.4 Hz, CH3 chain), 3.93-4.05 (as, CH2-NH-Gua, CH2 terminal ), 4.10-4.23 (ad, CH2B-N (Gua) -CH2B, Yes, b = 12.4 Hz, CH2B chain), 4.29-4.39 (m, CHza a-Gua), 4.45-4.52 (m, CH 2 B cr-Gua), 7.30-7.83 (m, = CH Ar), 8.08 (as, N = CH). 13 C-NMR (D 2 O), δ (ppm): 46.25, 46.56, 46.94 (CH 2 α-Gua), 56.90, 56.97, 57.03 (CH 2 terminal), 63.87, 64.02 (CH2-N (Gua) -CH2 chain), 128.93, 129.04, 129.57, 129.63, 129.78, 129.84, 130.20, 130.32, 130.49, 130 , 66,132,10, 132,17, 132,30, 132,40, 132,62, 132,67, 132, 75, 132,83, 132,92, 133,20 (CH Ar), 135,02, 135 , 19, 137, 54, 137, 92, 138, 133, 138, 50, 139, 07, 139, 23, 141, 31, 142, 53 (Cq Ar), 150, 21, 151, 05, 151, 12 (N = CH), 157.60, 159.67, 159.73, 160.85 (Cq Gua).
The peaks at 3.72-3.91 ppm and 4.10-4.23 ppm in the 1H spectrum and at 64.02 ppm in the 13C spectrum confirm the presence of a di-substituted nitrogen atom of the aminoguanidine.
Example 2
Preparation of Polvaminoquanidine (2)
In a manner analogous to Example 1, polyguanidine (2) was obtained as a yellowish, amorphous solid from α, α'-dichloro-m-xylene and aminoguanidine hydrochloride. 1H-NMR (D20), δ (ppm): 3.73-3.92 (ad, CH2A-N (Gua) -CH2A, Ab = 12.7 Hz, CH2A chain), 3.94-4.05 ( as, CH2-NH-Gua, CH2 terminal), 4.10-4.23 (ad, CH2B-N (Gua) -CH2B, JAβ = 12.7 Hz, CH2B chain), 4.29-4.38 ( m, CHm a-Gua), 4.45-4.53 (m, CH 2 B a-Gua), 7.23-7.85 (m, = CH Ar), 8.10 (as, N = CH). 13C-NMR (D20), δ (ppm): 46.36, 46.66, 47.01 (CH2 a-Gua), 57.01, 57.04, 57.12, 57.14 (CH2 terminal), 63.94 (CH 2 -N (Gua) -CH 2 chain), 129.63, 129.75, 130.09, 130.20, 130.83, 131.38, 131.44, 131.53, 131.57 , 131.67, 131.82, 131.89, 132.18, 132.34, 132.73, 133.52, 134.23, 134.52, 135.29 (CH Ar), 135.72, 135 , 81, 136,12, 138,59,138,69,138,73,139,13, 139,77, 139,90, 140,30 (Cq Ar), 151,24 (N = CH), 157,67,159,78,159,81, 160.86 (Cq Gua).
The peaks at 3.73-3.92 ppm and 4.10-4.23 ppm in the 1H spectrum and at 63.94 ppm in the 13C spectrum again confirm the presence of a doubly substituted nitrogen atom of the aminoguanidine.
Example 3
Preparation of Polvaminoquanidine (3)
In a manner analogous to Example 2, 132 mg (0.5 mmol) of α, α'-dibromo-m-xylene (in place of the dichloro derivative) and 1.75 equivalents of aminoguanidine hydrochloride (97 mg, 0.88 mmol) polyguanidine (3) as a brownish, amorphous solid. 1 H-NMR (D 2 O), δ (ppm): 3.63-3.95 (m, CH 2 -NiGuay-CH 2, CH 2 A chain), 3.95-4.08 (as, CH 2 -NH-Gua, CH2 terminal), 4.13-4.24 (ad, CH2B-N (Gua) -CH2B, Yes, b = 12.5Hz, CH2B chain), 4.31-4.40 (m, CH2A a-Gua ), 4.47-4.55 (m, CH2B a-Gua), 7.17-7.86 (m, -CH Ar), 8.12 (as, N = CH). 13 C-NMR (D 2 O), δ (ppm): 46.38, 46.64, 46.99 (CHZ a-Gua), 56.98, 57, 11, 57, 48 (CH 2 terminal), 63.90 ( CH2-N (gua) -CH2 chain), 128.58, 129.08, 129.64, 129.76, 130.05, 130.20, 130.81, 130.98, 131.35, 131.41, 131.51 , 131, 71, 131, 80, 131, 87, 132, 16, 132, 33, 132, 69, 133, 49, 134, 21, 134, 51, 135, 29 (CH Ar), 135, 66, 135 , 76, 136.06, 138.68, 138.98, 139.07, 139.25, 139.72, 139.85, 140.25 (Cq Ar), 150.46, 151.29 (N = CH ), 159.73, 160.84 (Cq Gua).
The peaks at 3.63-3.95 ppm and 4.13-4.24 ppm in the 1H spectrum and at 63.90 ppm in the 13C spectrum again confirm the presence of a doubly substituted nitrogen atom of the aminoguanidine.
Example 4
Preparation of Polvdiaminoauanidine (4)
In a manner analogous to Example 2, from 88 mg (0.5 mmol) of α, α'-dichloro-m-xylene and 1 equivalent of diaminoguanidine hydrochloride (68 mg, 0.5 mmol) polyguanidine (4) as yellowish, obtained amorphous solid.
The structure determination by means of 1H and 13C NMR also indicated the presence of doubly substituted nitrogen atoms, whereby it can be assumed that also non-negligible proportions of crosslinked product were formed in which the second terminal nitrogen of Diaminoguanidins is integrated into another chain. The verification of the proportions of cross-linked and uncrosslinked product is currently pending.
Example 5
Preparation of Polvauanidine (5)
In a manner analogous to Example 3, from 132 mg (0.5 mmol) of α, α'-dibromo-p-xylene and 1.75 equivalents of guanidine hydrochloride (83 mg, 0.88 mmol) polyguanidine (5) was used as reddish, amorphous solid.
Structure elucidation by 1H and 13C NMR also indicated in this case the presence of doubly substituted nitrogen atoms, although comparable amounts of polyguanidine with only singly substituted nitrogen atoms of the following formula were also detected:
Due to the density of the signals, the verification of the exact proportions of singly and doubly substituted nitrogen atoms in the product is still pending.
Veraleich example 1
Preparation of a polyaminoguanidine from diamine and aminoguanidine
23 mmol of 1,3-diaminoguanidinium hydrochloride and 24 mmol of 4,9-dioxadodecane-1,12-diamine were heated in a closed reaction tube with a drying tube for 90 minutes with stirring to 120 ° C, then the temperature for 100 min on 180 ° C, of which at the end of this reaction time for 45 min under reduced pressure (50 mbar). After cooling the reaction mixture to below 80 ° C, 25 ml of water were added to the gel-like reaction product. After a few hours a clear solution was obtained.
From a sample of the resulting aqueous solution, the water was evaporated and the resulting residue was dried in vacuo to give a reddish viscous liquid. This was dissolved in 2 ml of D20 (with a degree of deuteration> 99.5%) and a 1H nuclear magnetic resonance (1H NMR) spectrum was recorded. The position of the thus distinguishable groups of methylene protons of Ri in the product is as follows: 1H-NMR (D20), δ (ppm): 1.54-1.67 (m, 0CH2C ^ CH2CH20), 1, 80-1.95 (m, NCH2CH2), 3.23-3.38 ppm (m, NCHg), 3.42-3.65 ppm (m, CHaCW2OCH2CH2).
This confirms the structure of the diamine component used, 4,9-dioxadodecane-1,12-diamine.
Example 6
Activity Determination: Antimicrobial / Antifungal / Antiviral Activity The activity of the new compounds was tested in multiple screening systems. The antibacterial and antifungal activity was assayed by MIC assay. MIC stands for the " minimal inhibitory concentration " (MIC for "minimal inhibitory concentration") and refers to the lowest concentration of a substance that can not be detected by the naked eye reproduction of microorganisms. The MIC is determined by a so-called titer method in which the substance is diluted out and then the pathogen is added.
As a rule, this determines the concentration of an antibiotic that just barely inhibits the growth of a bacterial strain. The MIC is expressed in micrograms per milliliter (pg / ml) or in vol.%, And the dilutions are made in the
Usually in log2 steps. Here, a starting concentration of 1% was diluted to double each, thus giving test concentrations of 0.5%, 0.25%, 0.125% and so on. Lower values therefore reflect better activity as an anti-infective agent.
The tests were performed according to the standards required by the EUCAST (European Committee for Antimicrobial Susceptibility Testing) and according to the AFST ("Antifungal Susceptibility Testing") regulations of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID).
The virus screening system is an infection system in which host cells are infected in vitro and the test substance is added before or after infection and its activity determined. All of these tests were performed according to the standard operating procedures of SeaLife Pharma for drug screening using analogous dilution series as in the antibacterial / antifungal assay.
In the overlay tables 1 to 3, the test results regarding the anti-infective effect of the novel compounds according to the invention from Examples 1, 3, 4 and 5 and of Comparative Example 1 against some multidrug-resistant bacteria and fungi as well as viruses are indicated. The data are each averages of multiple determinations.
It will be appreciated that the novel compounds of the invention show excellent activity against both Gram-positive and Gram-negative agents.
Example 7
toxicity tests
It can also be seen from the accompanying FIG. 1 that the novel polyguanidines according to the invention exhibit at the same time extremely low toxicity in those concentrations in which they have excellent antimicrobial activity, as shown by the proportion of surviving cells of the exposed HaCaT cell line as cell model on the Y-axis clear.
Table 1 - Action against gram-positive and -negative pathogens
Table 2 - Action against fungi and yeasts
Table 3 - Effect against viruses

权利要求:
Claims (20)
[1]
PATENT CLAIMS 1. A process for preparing polycondensation products of guanidine, aminoguanidine or diaminoguanidine G with one or more benzylic dihalides BDH according to the following reaction scheme:

wherein each X is a halogen, preferably chlorine or bromine; Ri is an aromatic ring system having at least one aromatic ring optionally containing one or more heteroatoms selected from Ο, N and S; Gua is a guanidinediyl-aminoguanidine diyl or diaminoguanidinediyl radical; Y stands for H-Gua and Z stands for H; or Y and Z together represent a chemical bond to give a cyclic structure; wherein at least one benzylic dihalide BDH is subjected to a polycondensation reaction with an excess of guanidine, aminoguanidine or diaminoguanidine G with elimination of HX to form a polyguanidine of the following formula (I), (II) or (III):

or with a cyclic structure obtained by ring closure with elimination of a corresponding guanidine, or to give a salt of the polyguanidine.
[2]
2. The method according to claim 1, characterized in that Ri is selected from divalent radicals of optionally substituted benzene, furan, pyrrole, thiophene, pyridine and biphenyl.
[3]
3. The method according to claim 2, characterized in that Ri is selected from divalent radicals of benzene, biphenyl and fluorene.
[4]
4. The method according to any one of claims 1 to 3, characterized in that the at least one benzylic dihalide BDH is reacted with guanidine, aminoguanidine or diaminoguanidine G by heating the reactants to a temperature above their melting temperatures.
[5]
5. The method according to any one of claims 1 to 4, characterized in that the reaction over a period of at least 2 h, preferably at least 3 h, is performed.
[6]
6. Polyguanidine corresponding to the following formula (I):

wherein Ri is an aromatic ring system having at least one aromatic ring which optionally contains one or more heteroatoms selected from Ο, N and S, or which has a cyclic structure obtained by ring closure with elimination of a guanidine.
[7]
7. Polyguanidine corresponding to the following formula (II):

wherein Ri is an aromatic ring system having at least one aromatic ring which optionally contains one or more heteroatoms selected from Ο, N and S, or which has a cyclic structure obtained by ring closure with the elimination of an aminoguanidine.
[8]
8. Polyguanidine corresponding to the following formula (III):

wherein Ri is an aromatic ring system having at least one aromatic ring optionally containing one or more heteroatoms selected from Ο, N and S, or having a cyclic structure obtained by ring closure to eliminate a diaminoguanidine.
[9]
9. Polyguanidine according to one of claims 6 to 9, characterized in that Ri is selected from divalent radicals of optionally substituted benzene, furan, pyrrole, thiophene, pyridine and biphenyl.
[10]
10. Polyguanidine according to claim 9, characterized in that Ri is selected from bivalent radicals of benzene, biphenyl and fluorene.
[11]
A polyguanidine as defined in any one of claims 6 to 10 for use as an antibiotic.
[12]
12. Polyguanidine for use according to claim 11, characterized in that the polyguanidine serves to combat bacterial infections in a human or animal patient.
[13]
Polyguanidine for use according to claim 12, characterized in that the polyguanidine is for topical or systemic administration.
[14]
Polyguanidine for use according to claim 13, characterized in that the polyguanidine is for administration in the form of a drug or a pharmaceutical composition.
[15]
Use of a polyguanidine as defined in any one of claims 6 to 10 as an antimicrobial ex vivo.
[16]
16. Use according to claim 15, characterized in that the polyguanidine serves as the active component of antimicrobial paints, coatings, films or membranes.
[17]
17. A pharmaceutical or pharmaceutical composition for controlling bacterial infections in a human or animal patient, which comprises a polyguanidine according to any one of claims 6 to 10 as an antibiotic.
[18]
A pharmaceutical or pharmaceutical composition according to claim 17, characterized in that it further comprises at least one pharmaceutically acceptable carrier or excipient and optionally one or more adjuvants and / or one or more other active ingredients.
[19]
19. A pharmaceutical or pharmaceutical composition according to claim 18, characterized in that it / at least one other active ingredient, which also acts antimicrobial.
[20]
A pharmaceutical or pharmaceutical composition according to claim 18 or 19, characterized in that it comprises at least one other active ingredient which is active against a condition other than a bacterial infection. Vienna, July 31, 2014

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同族专利:

公开号 | 公开日

CN106715387A|2017-05-24|

US10335431B2|2019-07-02|

US20190269719A1|2019-09-05|

PT3174848T|2018-11-29|

EA035565B1|2020-07-08|

JP2017530211A|2017-10-12|

EP3174848A1|2017-06-07|

SI3174848T1|2019-03-29|

WO2016015081A1|2016-02-04|

EP3174848B1|2018-08-01|

HUE041586T2|2019-05-28|

WO2016015081A9|2016-03-31|

TR201816160T4|2018-12-21|

SG11201700749VA|2017-02-27|

PL3174848T3|2019-05-31|

AU2015296881A1|2017-02-23|

BR112017002094A2|2017-11-21|

PH12017500186A1|2017-06-28|

JP6723221B2|2020-07-15|

US20170224723A1|2017-08-10|

AU2015296881B2|2020-01-02|

HRP20181805T1|2019-03-22|

PH12017500186B1|2017-06-28|

CY1121425T1|2020-05-29|

US11013760B2|2021-05-25|

ES2699185T3|2019-02-07|

EA201790249A1|2017-07-31|

DK3174848T3|2018-11-26|

AT516070B1|2016-08-15|

CN106715387B|2019-07-12|

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法律状态:
2021-03-15| MM01| Lapse because of not paying annual fees|Effective date: 20200731 |

优先权:

申请号 | 申请日 | 专利标题

ATA609/2014A|AT516070B1|2014-07-31|2014-07-31|Process for the preparation of polyguanidines|ATA609/2014A| AT516070B1|2014-07-31|2014-07-31|Process for the preparation of polyguanidines|

CN201580051065.1A| CN106715387B|2014-07-31|2015-07-30|The method for preparing polyguanidine|

US15/500,772| US10335431B2|2014-07-31|2015-07-30|Method for producing polyguanidines|

SI201530459T| SI3174848T1|2014-07-31|2015-07-30|Method for producing polyguanidines|

DK15771843.8T| DK3174848T3|2014-07-31|2015-07-30|Process for the preparation of polyguanidines|

EA201790249A| EA035565B1|2014-07-31|2015-07-30|Method for producing polyguanidine|

JP2017505529A| JP6723221B2|2014-07-31|2015-07-30|Method for producing polyguanidine|

PL15771843T| PL3174848T3|2014-07-31|2015-07-30|Method for producing polyguanidines|

EP15771843.8A| EP3174848B1|2014-07-31|2015-07-30|Method for producing polyguanidines|

AU2015296881A| AU2015296881B2|2014-07-31|2015-07-30|Method for producing polyguanidines|

PCT/AT2015/050187| WO2016015081A1|2014-07-31|2015-07-30|Method for producing polyguanidines|

PT15771843T| PT3174848T|2014-07-31|2015-07-30|Method for producing polyguanidines|

TR2018/16160T| TR201816160T4|2014-07-31|2015-07-30|PRODUCTION PROCEDURE OF POLYGUANIDINS.|

BR112017002094A| BR112017002094A2|2014-07-31|2015-07-30|method for production of polyguanidines|

ES15771843T| ES2699185T3|2014-07-31|2015-07-30|Procedure for the preparation of polyguanidines|

PH12017500186A| PH12017500186B1|2014-07-31|2017-01-31|Method for producing polyguanidines|

CY20181101138T| CY1121425T1|2014-07-31|2018-11-01|METHOD FOR THE PREPARATION OF POLYGUANIDS|

US16/411,703| US11013760B2|2014-07-31|2019-05-14|Polyguanidine polymers and methods of use thereof|

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