METHOD FOR PRODUCING POLYGUANIDINES

Abstract

A method for preparing polycondensation products of guanidine, aminoguanidine or diaminoguanidine G with one or more benzyl or allyl derivatives BA according to the following reaction scheme is provided:

##STR00001##

wherein X, R.sub.1, Gua, Y and Z are as defined in the specification. In the disclosed method, at least one benzyl or allyl derivative BA is subjected to a polycondensation reaction with excessive guanidine, aminoguanidine or diaminoguanidine G upon elimination of HX.

Claims

1.-21. (canceled)

22. A method for preparing polycondensation products from guanidine, aminoguanidine or diaminoguanidine G with one or more benzyl or allyl derivatives BA according to the following reaction scheme: ##STR00028## wherein each X independently represents a leaving group; each R.sub.1 independently represents either an aromatic ring system with at least one aromatic ring, optionally containing one or more hetero atoms selected from the group consisting of O, N and S and optionally being substituted with one or two vinyl groups to which the —CH.sub.2—X group(s) is/are bound, or represents ethylene; 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 obtain a cyclic structure; and n is ≧2; wherein at least one benzyl or allyl derivative BA is subjected to a polycondensation reaction with excessive guanidine, aminoguanidine or diaminoguanidine G upon elimination of HX in order to provide a polyguanidine corresponding to the following formula (I), (II) or (III): ##STR00029## or having a cyclic structure resulting from cyclization upon elimination of a corresponding guanidine, or a salt of said polyguanidine.

23. The method of claim 22, wherein R.sub.1 is a divalent residue selected from the group consisting of optionally substituted benzene, divinylbenzene, furan, pyrrole, thiophene, pyridine, biphenyl, fluorene and ethylene.

24. The method of claim 23, wherein R.sub.1 is a divalent residue selected from the group consisting of benzene, divinylbenzene, pyridine, biphenyl and ethylene.

25. The method of claim 22, wherein the leaving group is selected from the group consisting of chlorine, bromine, iodine, mesylate, triflate and tosylate.

26. The method of claim 22, wherein the at least one benzyl or allyl derivative BA is reacted with guanidine, aminoguanidine or diaminoguanidine G by heating the reactants at a temperature above their melting temperatures.

27. The method of claim 22, wherein the reaction is conducted for a period of at least 2 h.

28. A polyguanidine of the following formula (I): ##STR00030## wherein R.sub.1 represents either an aromatic ring system with at least one aromatic ring, optionally containing one or more heteroatoms selected from the group consisting of O, N and S and optionally being substituted with one or two vinyl groups to which the —CH.sub.2—X group(s) is/are bound, or represents ethylene, and wherein n is ≧2; or having a cyclic structure resulting from cyclization upon elimination of a corresponding guanidine, or a salt of said polyguanidine.

29. A polyguanidine of the following formula (II): ##STR00031## wherein R.sub.1 represents either an aromatic ring system with at least one aromatic ring, optionally containing one or more heteroatoms selected from the group consisting of O, N and S and optionally being substituted with one or two vinyl groups to which the —CH.sub.2—X group(s) is/are bound, or represents ethylene, and wherein n is ≧2; or having a cyclic structure resulting from cyclization upon elimination of a corresponding guanidine, or a salt of said polyguanidine.

30. A polyguanidine of the following formula (III): ##STR00032## wherein R.sub.1 represents either an aromatic ring system with at least one aromatic ring, optionally containing one or more heteroatoms selected from the group consisting of O, N and S and optionally being substituted with one or two vinyl groups to which the —CH.sub.2—X group(s) is/are bound, or represents ethylene, and wherein n is ≧2; or having a cyclic structure resulting from cyclization upon elimination of a corresponding guanidine, or a salt of said polyguanidine.

31. The polyguanidine of claim 28, wherein R.sub.1 is a divalent residue selected from the group consisting of optionally substituted benzene, divinylbenzene, furan, pyrrole, thiophene, pyridine, biphenyl, fluorene and ethylene.

32. The polyguanidine of claim 31, wherein R.sub.1 is a divalent residue selected from the group consisting of benzene, divinylbenzene, pyridine, biphenyl and ethylene.

33. A method of treating an infection in a human or animal patient, the method comprising administering to the human or animal patient the polyguanidine as defined in claim 22.

34. The method of claim 33, wherein the infection is a bacterial, viral or fungal infection.

35. The method of claim 34, wherein the polyguanidine is administered topically or systemically.

36. The method of claim 35, wherein the polyguanidine is administered in the form of a drug or a pharmaceutical composition.

37. A method of using the polyguanidine as defined in claim 28 as an ex vivo antimicrobial agent.

38. The method of claim 37, wherein the polyguanidine is an active component of antimicrobial paints, coatings, foils, or membranes.

39. A drug or pharmaceutical composition for antagonizing bacterial infections in a human or animal patient comprising a polyguanidine of claim 28 as an antiinfective.

40. The drug or pharmaceutical composition of claim 39, further comprising at least one pharmaceutically acceptable carrier or excipient and optionally one or more adjuvants and/or one or more further active agents.

41. The drug or pharmaceutical composition of claim 40, comprising at least one further active agent that also shows an antiinfective effect.

42. The drug or pharmaceutical composition of claim 40, comprising at least one further active agent that is effective against a condition other than bacterial infections.

Description

EXAMPLES

Example 1

[0060] Preparation of Polyaminoguanidine (1)

##STR00013##

[0061] α,α′-Dichloro-p-xylene (880 mg, 5.03 mmol) and 1.95 equivalents of aminoguanidine hydrochloride (1083 mg, 9.80 mmol) were heated with stirring to 160° C. for 3 h in an open reaction vessel, followed by heating to 180° C. for 2 h. After the reaction mixture had cooled to below 80° C., the tenfold amount of water was added to the reaction product, and after thoroughly mixing by means of stirring or ultrasound treatment, a clear, light yellow solution with traces of solid contents was obtained. It was filtered through a 0.2 μm PFTE membrane and then evaporated to obtain polyguanidine (1) as a yellow, amorphous solid.

[0062] For analysis, a sample was dissolved in a tenfold amount of D.sub.2O. When recording the .sup.1H and the .sup.13C NMR spectra, DSS (4,4-dimethyl-4-silapentane-1-sulfonic acid) was added for reference as an internal standard:

[0063] .sup.1H NMR (D.sub.2O), δ (ppm): 3.72-3.91 (ad, CH.sub.2A—N(Gua)-CH.sub.2A, J.sub.A,B=12.4 Hz, CH.sub.2A chain), 3.934.05 (as, CH.sub.2—NH-Gua, CH.sub.2 terminal), 4.10-4.23 (ad, CH.sub.2B—N(Gua)-CH.sub.2B, J.sub.A,B=12.4 Hz, CH.sub.2B chain), 4.29-4.39 (m, CH.sub.2A α-Gua), 4.45-4.52 (m, CH.sub.2B α-Gua), 7.30-7.83 (m, ═CH Ar), 8.08 (as, N═CH).

[0064] .sup.13C NMR (D.sub.2O), δ (ppm): 46.25, 46.56, 46.94 (CH.sub.2 α-Gua), 56.90, 56.97, 57.03 (OCH.sub.2 terminal), 63.87, 64.02 (CH.sub.2—N(Gua)-CH.sub.2 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, 138.13, 138.50, 139.07, 139.23, 141.31, 142.53 (C.sub.q Ar), 150.21, 151.05, 151.12 (N═CH), 157.60, 159.67, 159.73, 160.85 (C.sub.q Gua).

[0065] The NMR signals in the ranges of 3.72-3.91 ppm and 4.10-4.23 ppm (H axis) and at 64.02 ppm (.sup.13C axis) confirm the presence of a doubly substituted nitrogen atom of the aminoguanidine.

[0066] MALDI-MS—MALDI-TOF (in the positive ion mode (matrix suppression off)); scan 20-3000 m/z (deflection off); matrix: ACH (α-cyano-4-hydroxy cinnamic acid); (m/z): 247.3, 249.3, 251.4, 425.3, 427.3, 601.4, 603.4, 777.5, 779.5, 953.7, 955.7, 1129.8, 1131.9, 1306.0, 1308.0, 1482.1, 1484.1, 1658.0, 1660.0, 1834.1, 1836.1, 2010.2, 2012.2, 2186.3, 2188.3, 2362.4.

Example 2

Preparation of Polyaminoguanidine (2)

[0067] ##STR00014##

[0068] In analogy to Example 1, polyguanidine (2) was prepared from α,α′-dichloro-m-xylene and aminoguanidine hydrochloride, yielding a yellowish, amorphous, completely water-soluble solid.

[0069] .sup.1H NMR (D.sub.2O), δ (ppm): 3.73-3.92 (ad, CH.sub.2A—N(Gua)-CH.sub.2A, J.sub.A,B=12.7 Hz, CH.sub.2A chain), 3.94-4.05 (as, CH.sub.2—NH-Gua, CH.sub.2 terminal), 4.10-4.23 (ad, CH.sub.2B—N(Gua)-CH.sub.2B, J.sub.A,B=12.7 Hz, CH.sub.2B chain), 4.29-4.38 (m, CH.sub.2A α-Gua), 4.45-4.53 (m, CH.sub.2B α-Gua), 7.23-7.85 (m, ═CH Ar), 8.10 (as, N═CH).

[0070] .sup.13C NMR (D.sub.2O), δ (ppm): 46.36, 46.66, 47.01 (CH.sub.2 α-Gua), 57.01, 57.04, 57.12, 57.14 (CH.sub.2 terminal), 63.94 (CH.sub.2—N(Gua)-CH.sub.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 (C.sub.q Ar), 151.24 (N═CH), 157.67, 159.78, 159.81, 160.86 (C.sub.q Gua).

[0071] The NMR signals in the ranges of 3.73-3.92 ppm and 4.10-4.23 ppm (.sup.1H axis) and at 63.94 ppm (.sup.13C axis) again confirm the presence of a doubly substituted nitrogen atom of the aminoguanidine.

[0072] MALDI-MS—MALDI-TOF (m/z): 247.3, 249.3, 251.4, 425.3, 427.3, 601.4, 603.4, 777.5, 779.5, 953.7, 955.7, 1129.8, 1131.9, 1306.0, 1308.0, 1482.1, 1484.1, 1658.0, 1660.0, 1834.1, 1836.1, 2010.2, 2012.2, 2186.3, 2188.3.

Example 3

Preparation of Polyamino Guanidine (3)

[0073] ##STR00015##

[0074] In analogy to Example 2, polyguanidine (3) was prepared from 132 mg (0.5 mmol) of α,α′-dibromo-m-xylene (instead of the dichloro derivative) as well as 1.75 equivalents of aminoguanidine hydrochloride (97 mg, 0.88 mmol), yielding a brownish, amorphous, water-soluble solid.

[0075] .sup.1H NMR (D.sub.2O), δ (ppm): 3.63-3.95 (m, CH.sub.2A—N(Gua)-CH.sub.2A, CH.sub.2A chain), 3.95-4.08 (as, CH.sub.2—NH-Gua, CH.sub.2 terminal), 4.13-4.24 (ad, CH.sub.2B—N(Gua)-CH.sub.2B, J.sub.A,B=12.5 Hz, CH.sub.2B chain), 4.31-4.40 (m, CH.sub.2A α-Gua), 4.47-4.55 (m, CH.sub.2B α-Gua), 7.17-7.86 (m, ═CH Ar), 8.12 (as, N═CH).

[0076] .sup.13C NMR (D.sub.2O), δ (ppm): 46.38, 46.64, 46.99 (CH.sub.2 α-Gua), 56.98, 57.11, 57.48 (CH.sub.2 terminal), 63.90 (CH.sub.2—N(Gua)-CH.sub.2 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 (C.sub.q Ar), 150.46, 151.29 (N═CH), 159.73, 160.84 (C.sub.q Gua).

[0077] The NMR signals in the ranges of 3.63-3.95 ppm and 4.13-4.24 ppm (.sup.1H axis) and at 63.90 ppm (.sup.13C axis) again confirm the presence of a doubly substituted nitrogen atom of the aminoguanidine.

[0078] MALDI-MS—MALDI-TOF (m/z): 247.3, 249.3, 251.4, 425.3, 427.3, 601.4, 603.4, 777.5, 779.5, 953.7, 955.7, 1129.8, 1131.9, 1306.0, 1308.0, 1482.1, 1484.1, 1658.0, 1660.0, 1834.1, 1836.1, 2010.2, 2012.2, 2186.3, 2188.3.

Example 4

Preparation of Polydiamino Guanidine (4)

[0079] ##STR00016##

[0080] In analogy to Example 2, polyguanidine (4) was prepared from 88 mg (0.5 mmol) of α,α′-dichloro-m-xylene and 1 equivalent of diaminoguanidine hydrochloride (68 mg, 0.5 mmol), yielding a yellowish, amorphous, water-soluble solid.

[0081] The structural determination by means of .sup.1H and .sup.13C NMR shows, in addition to the product species found in the Examples 1 to 3, also the presence of larger proportions of highly branched components in which another guanidine nitrogen is benzylized beyond the imino functionality.

Example 5

Preparation of Polyguanidine (5)

[0082] ##STR00017##

[0083] In analogy to Example 3, polyguanidine (5) was prepared from 132 mg (0.5 mmol) of α,α′-dibromo-p-xylene and 1.75 equivalents of guanidine hydrochloride (83 mg, 0.88 mmol), yielding a water-soluble, reddish, amorphous solid.

[0084] The structural determination by means of .sup.1H and .sup.13C NMR shows, in addition to the product species found in the Examples 1 to 3, also the presence of larger proportions of highly branched components in which another guanidine nitrogen is benzylized beyond the imino functionality.

[0085] MALDI-MS—MALDI-TOF (m/z): 355.3, 382.3, 516.4, 543.4, 677.3, 704.5, 838.5, 865.5, 999.6, 1026.6, 1160.7, 1187.7, 1321.8, 1348.8, 1483.9, 1510.9, 1672.0, 1833.1, 1995.2.

Example 6

Preparation of Polyaminoguanidine (6)

[0086] ##STR00018##

[0087] 2,6-Bis(bromomethyl)pyridine (265 mg, 1 mmol) and 1.95 equivalents of aminoguanidine hydrochloride (216 mg, 1.95 mmol) were heated with stirring to 160° C. for 1.5 h in an open reaction vessel, followed by heating to 180° C. for 1.5 h. After the reaction mixture had cooled to below 80° C., water (4.81 ml) was added to the reaction product, and after thoroughly mixing by means of stirring or ultrasound treatment as well as filtration through a 0.2 μm PFTE membrane, a clear, dark brown solution was obtained.

[0088] MALDI-MS—MALDI-TOF (m/z): 248.4, 250.4, 252.4, 421.4, 423.4, 425.4, 427.4, 429.4, 598.4, 600.4, 602.4, 604.4.

Example 7

Preparation of Polyaminoguanidine (7)

[0089] ##STR00019##

[0090] In analogy to Example 2, polyguanidine (7) was prepared from 4,4′-bis(chloromethyl)biphenyl (251 mg, 1 mmol) as well as 1.95 equivalents of aminoguanidine hydrochloride (216 mg, 1.95 mmol), yielding a yellowish, amorphous solid, which is, apart from small amounts of a solid residue, easily soluble in water.

[0091] MALDI-MS—MALDI-TOF (m/z): 323.4, 325.4, 327.4, 575.4, 577.4, 579.4, 827.6, 829.6, 831.6.

Example 8

Preparation of Polyaminoguanidine (8)

8.1 Preparation of dimethyl-3,3′-(1,3-phenylene)-(2E,2′E)-diacrylate

[0092] ##STR00020##

[0093] To a solution of 0.75 mmol of isophthalic aldehyde in 10 ml THF, a solution of 2.05 equivalents of (methoxycarbonylethylene)triphenylphosphorane (1.54 mmol) in 15 ml THF was added with the exclusion of air. The reaction mixture was stirred for 12 h at 50° C. and then concentrated. A chromatographic purification (silica, dichloromethane) yielded: 0.62 mmol (83% o.th.) of a white solid.

[0094] .sup.1H NMR (400 MHz, CDCl.sub.3): 3.82 (s, 6H), 6.47 (d, J=16 Hz, 2H), 7.42 (dd, J=7.7+7.7 Hz, 1H), 7.54 (dd, J=7.7+1.7 Hz, 2H), 7.64 (t, J=1.7 Hz, 1H), 7.69 (d, J=16 Hz, 2H).

8.2 Preparation of (2E,2′E)-3,3′-(1,3-phenylene)-bis(prop-2-en-1-ole)

[0095] ##STR00021##

[0096] In a Schlenk vessel, 1.50 mmol of dimethyl-3,3′-(1,3-phenylene)-(2E,2′E)-diacrylate were dissolved in 30 ml anhydrous dichloromethane. At −78° C., 4.5 equivalents of diisobutylaluminum hydride were slowly added dropwise as a 1 M solution in toluene (6.75 ml). The reaction mixture was stirred for 2 h at −78° C. and subsequently hydrolyzed at 0° C. with methanol. The resulting white precipitate was filtered, the filtrate was concentrated and chromatographically purified (silica, DCM:EE 1:1), with 1.05 mmol (70% o.th.) of a white solid being isolated.

[0097] .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm): 4.26 (m, 4H), 6.33 (dm, J=16 Hz, 2H), 6.56 (br, d, J=16 Hz, 2H), 7.22 (m, 3H), 7.34 (br s, 1H).

8.3 Preparation of 1,3-bis((E-3-chloroprop-1-en-1-yl)benzene

[0098] ##STR00022##

[0099] In a Schlenk vessel, 0.95 mmol of dimethyl-3,3′-(1,3-phenylene)-(2E,2′E)-diacrylate and 3 equivalents of diisopropylethylamine (DIPEA, 2.85 mmol) in 20 ml dichloromethane were provided and cooled to −40° C., followed by the addition of 2.38 mmol of methanesulfonyl chloride and stirring of the reaction mixture at room temperature for 12 h. After withdrawal of the solvent, the crude product was purified chromatographically (silica, DCM), with 0.57 mmol (60% o.th.) of a white, crystalline solid being isolated.

[0100] .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm): 4.25 (dd, J=7.1+1.2 Hz, 4H), 6.34 (dt, J=15.7+7.1 Hz, 2H), 6.65 (dt, J=15.7+1.2 Hz, 2H), 7.30 (m, 3H), 7.40 (m, 1H).

8.4 Preparation of Polyaminguanidine (8)

[0101] ##STR00023##

[0102] In analogy to Example 2, polyguanidine (8) was prepared from 1,3-bis((E)-2-chlorovinyl)benzene (200 mg, 1 mmol) and 1.95 equivalents of aminoguanidine hydrochloride (216 mg, 1.95 mmol), yielding a yellowish, translucent, water-soluble gel.

[0103] MALDI-MS—MALDI-TOF (m/z): 303.3, 531.4, 759.6, 833.7, 987.8, 1061.9, 1216.0.

Example 9

Preparation of Polyaminoguanidine (9)

9.1 Preparation of cis-1,4-bis(methylsulfonyloxy)but-2-ene

[0104] ##STR00024##

[0105] 10 g of cis-but-2-ene-1,4-diol (113 mmol) and 3.0 equivalents of diisopropylethylamine (44 g, 340 mmol, 60 ml) were dissolved in 250 ml of dichloromethane and cooled in an argon atmosphere to −40° C., after which 2.4 equivalents of methanesulfonyl chloride (30.9 g, 270 mmol, 20.9 ml) were added portionwise and the reaction mixture was allowed to warm up to +10° C. for 1 h. The clear, yellow solution was poured into 500 ml ice-cold water and the organic phase was washed with further 500 ml of cold water, then with 200 ml of 2 N HCl, then twice with 200 ml each of saturated NaHCO solution, and finally again twice with 200 ml each of water. The dichloromethane solution of the product was dried over Na.sub.2SO.sub.4 and the solvent was withdrawn in vacuo until a white precipitate appeared, whereafter the minimum amount of dichloromethane was added in order to again obtain a clear solution. After the addition of 25 ml of diethylether, the product was left to crystallize from the solution at −20° C., whereafter 10 g of cis-1,4-bis(methylsulfonyloxy)-but-2-ene were isolated as a crystalline, white solid.

[0106] .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm): 3.04 (s, 3H), 4.84 (m, 2H), 5.95 (m, 1H). 9.2 Preparation of polyaminoguanidine (9)

##STR00025##

[0107] Cis-1,4-bis(methylsulfonyloxy)but-2-ene (246 mg, 1 mmol) and 1.95 equivalents of aminoguanidine hydrochloride (216 mg, 1.95 mmol) were heated in a closed vessel in an argon atmosphere with stirring to 160° C. for 3 h, then to 180° C. for 2 h. After the reaction mixture had cooled to below 80° C., water (4.67 ml) was added to the reaction product to obtain a clear, yellow-red solution.

[0108] MALDI-MS—MALDI-TOF (m/z): 201.3, 251.3, 253.3, 297.2, 325.3, 327.3, 349.2, 377.3, 423.3, 451.3, 453.3, 519.3.

Preparation of Polyaminoguanidine (10)

[0109] ##STR00026##

[0110] 1,4-Dichloro-2-butene (262 mg, 1.3 mmol) and 1.95 equivalents of aminoguanidine hydrochloride (216 mg, 1.95 mmol) were heated in a closed reaction vessel in an argon atmosphere with stirring and repeated (three times per hour) replacement of the atmosphere with fresh argon to 150° C. for 2 h, then to 170° C. for 1 h. After the reaction mixture had cooled to below 80° C., water (4.67 ml) was added to the reaction product to obtain a clear, yellow-red solution.

[0111] MALDI-MS—MALDI-TOF (m/z): 201.3, 251.3, 253.3, 297.2, 325.3, 327.3, 377.3, 423.3, 451.3, 453.3.

Comparative Example 1

Preparation of a Polyaminoguanidine from Diamine and Aminoguanidine

[0112] ##STR00027##

[0113] 23 mmol of 1,3-diaminoguanidinium hydrochloride and 24 mmol of 4,9-dioxadodecane-1,12-diamine were heated to 120° C. in a reaction vessel closed with a drying tube for 90 min with stirring, whereafter the temperature was increased to 180° C. for 100 min, at the end of which reaction time the pressure was reduced for 45 min (50 mbar). After the reaction mixture had cooled 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.

[0114] The water was evaporated from a sample of the resulting aqueous solution and the obtained residue was dried in vacuum, yielding a reddish, viscous liquid. It was dissolved in 2 ml of D.sub.2O (with a deuteration degree >99.5%) and a .sup.1H nuclear resonance (.sup.1H NMR) spectrum was recorded. The position of the groups of methylene protons of the R.sub.1 residues thus distinguishable is as follows:

[0115] .sup.1H NMR (D.sub.2O), δ (ppm): 1.54-1.67 (m, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O), 1.80-1.95 (m, NCH.sub.2CH.sub.2), 3.23-3.38 ppm (m, NCH.sub.2), 3.42-3.65 ppm (m, CH.sub.2CH.sub.2OCH.sub.2CH.sub.2).

[0116] This confirms the structure of the diamine component used, 4,9-dioxadodecan-1,12-diamine.

Example 11

[0117] Activity Measurements: Antimicrobial/Antifungal/Antiviral Effect

[0118] The activity of the new compounds was tested in screening systems performed several times each. The antibacterial and antifungal activities were examined by means of an MIC test. MIC means “minimal inhibitory concentration” and refers to the lowest concentration of a substance at which no propagation of microorganisms is perceivable with the naked eye. The MIC is determined with a so-called titer process in which the substance is diluted and then the pathogen is added.

[0119] This normally serves to determine the concentration of an antibiotic that just inhibits the growth of a bacterial strain. Die MIC is expressed in micrograms per milliliter (μg/ml) or in % by volume, and the dilutions are normally conducted in log 2 steps.

[0120] Herein, a starting concentration of 1% was diluted twofold each time, leading to test concentrations of 0.5%, 0.25%, 0.125% etc. Lower values thus reflect better activity as antiinfective.

[0121] The tests were conducted according to the standards required by EUCAST (European Committee for Antimicrobial Susceptibility Testing) and according to the AFST (“Antifungal Susceptibility Testing”) provisions of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID).

[0122] The screening system for viruses is an infection system in which host cells are infected in vitro and the test substance is added before or after the infection, followed by the determination of its activity. All these tests were conducted according to internal standard rules of SeaLife Pharma for drug screening using analogous dilution series as in the antibacterial/antifungal test.

[0123] In the following Tables 1 to 3, test results regarding the antiinfective effects of the inventive new compounds from the Examples 1, 3, 4 and 5 and from Comparative Example 1 against several multiresistant bacteria and fungi as well as viruses are shown. The data are mean values of multiple determinations.

[0124] It is obvious that the new compounds of the invention show excellent activity against gram-positive as well as gram-negative pathogens.

Example 12

[0125] Toxicity Tests

[0126] Attached FIG. 1 further shows that the inventive new polyguanidines show very low toxicity at those concentrations at which they exhibit excellent antimicrobial activity, as is clearly shown by the proportion of surviving cells of the exposed HaCaT cell line as cell model on the Y axis.

TABLE-US-00001 TABLE 1 Effects against gram-positive and gram-negative pathogens MIC [%] Entero- Streptococcus Staphylococcus Klebsiella Entero- Pseudomonas Clostridium MRSA coccus pneumoniae epidermis E. coli pneumoniae bacter aeroginosa def. Salmonella Example 1 >0.0016 >0.0002 >0.0016 >0.0008 >0.0016 >0.025 >0.003 >0.003 >0.0008 >0.003 Example 2 >0.0008 >0.0008 >0.0008 >0.0002 >0.0008 >0.025 >0.0008 >0.0016 >0.0004 >0.0008 Example 3 >0.0004 >0.0008 >0.0008 >0.0004 >0.0008 n.d. >0.0016 >0.003 >0.0004 >0.0008 Example 4 >0.003 >0.003 >0.003 >0.0016 >0.0063 n.d. >0.0125 >0.0125 >0.003 >0.0125 Example 5 >0.0008 >0.0002 >0.0004 >0.0004 >0.0016 >0.0125 >0.0016 >0.003 >0.0004 >0.0016 Example 6 >0.025 >0.0125 >0.025 >0.025 >0.025 >0.05 >0.025 >0.025 >0.025 >0.05 Example 7 >0.0002 >0.0002 >0.0002 >0.0002 >0.0008 >0.0004 >0.0008 >0.0008 >0.0008 >0.0008 Example 8 >0.0004 >0.0004 >0.0004 >0.0004 >0.0008 >0.0008 >0.0008 >0.0008 >0.0008 >0.0008 Example 9 >0.0125 >0.003 >0.0125 >0.0125 >0.0008 >0.0008 >0.025 >0.025 >0.025 >0.025 Example 10 >0.0125 >0.0125 >0.0125 >0.0125 >0.025 >0.025 >0.025 >0.025 >0.025 >0.025 Comparative >0.001 >0.008 >0.004 >0.001 >0.016 >0.02 >0.008 >0.02 n.d. >0.03 example 1

TABLE-US-00002 TABLE 2 Effects against fungi and yeasts MIC [%] Tricho- Micros- Candida Candida Candida Candida Aspergillus Aspergilus Fusarium phyton Alternarria porum Dematiacea albicans papillosis glabrata krusei terreus fumigates rosei sp. sp. canis sp. Example 1 >0.025 >0.025 >0.025 >0.025 >0.05 >0.05 >0.05 >0.025 >0.025 >0.025 >0.025 Example 2 >0.025 >0.025 >0.025 >0.025 >0.05 >0.05 >0.025 >0.025 >0.05 >0.025 >0.05 Example 3 >0.025 >0.025 >0.025 >0.025 >0.05 >0.05 >0.025 >0.025 >0.05 >0.025 >0.05 Example 4 >0.05 >0.05 >0.05 >0.05 >0.1 >0.1 >0.1 >0.05 >0.05 >0.05 >0.1 Example 5 >0.025 >0.025 >0.025 >0.025 >0.05 >0.05 >0.025 >0.025 >0.05 >0.025 >0.05 Example 6 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 Example 7 >0.025 >0.025 >0.025 >0.025 >0.05 >0.05 >0.025 Example 8 >0.025 >0.025 >0.025 >0.025 >0.05 >0.05 >0.05 Example 9 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 Example 10 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 Comparative >0.008 >0.03 >0.02 >0.02 >0.02 >0.03 >0.03 >0.02 >0.02 >0.03 >0.02 example 1

TABLE-US-00003 TABLE 3 Effects against viruses Human MIC [%] Influenza A Influenza B Rhinovirus Example 1 >0.0016 >0.0016 >0.0016 Example 2 >0.0016 >0.0016 >0.0016 Example 3 >0.0016 >0.0016 >0.0016 Example 4 >0.003 >0.003 >0.003 Example 5 >0.0016 >0.0016 >0.0016 Example 6 >0.025 >0.05 >0.025 Example 7 >0.0016 >0.0016 >0.0016 Example 8 >0.0032 >0.0016 >0.0032 Example 9 >0.0125 >0.0125 >0.0125 Example 10 >0.0125 >0.0125 >0.0125 Comparative >0.035 >0.008 >0.008 example 1