TRIS-SUBSTITUTED BIGUANIDE COMPOUNDS AND THEIR USES

Abstract

Novel tris-substituted biguanide compounds are made by reaction of sodium dicyanamide with a trifunctional primary amine followed by reaction with anilines. The tris-substituted biguanide compounds are potent biocide and useful as a disinfectant. The novel compounds have biocidal activity comparable to those of widely used chlorhexidine with respect to width of antibacterial spectrum and in immediate effectiveness. The novel tris-substituted biguanide compounds can also be used for cleaning wounds, preventing dental plaque, treating yeast infections of the mouth, and to keep urinary catheters from blocking, These novel compounds have superior aqueous solubility and bioavailability and have potent antibacterial activity especially against A. baumanni and K. pneumonia.

Claims

1. A biocide solution comprising a compound having three substituted biguanide groups of the following formula: ##STR00010## wherein Linker represents linkage group with 3 or more points of connections for biguanide groups and; R1, R2, R3 represent independently the same or different alkyl, aryl or heterocyclic groups, optionally substituted with halogen, O—R4, N—R5R6, R7; R4, R5, R6, R7 represent independently the same or different alkyl or aryl groups, optionally substituted with halogen, O-alkyl; Cl.sup.− represent counter ions including chloride, bromide, iodide, acetate, or gluconate.

2. The biocide solution according to claim 1 comprising a compound having three substituted biguanide groups of the following formula: ##STR00011## wherein Linker represent linkage group with 3, or more points of connections for biguanide groups; X, Y, Z represent independently the same or different alkyl, O-alkyl, aryl or O-aryl groups, optionally substituted with halogen, O—R4, N—R5R6, R7; R4, R5, R6, R7 represent independently the same or different alkyl or aryl groups, optionally substituted with halogen, O-alkyl; and the Linker represents linkage groups of the following structures ##STR00012## wherein Cl.sup.− represent counter ions including chloride, bromide, iodide, acetate, or gluconate.

3. The biocide solution according to claim 2 wherein the compound has three substituted biguanide groups of the following formula: ##STR00013## wherein X, Y, Z represent independently the same or different alkyl, O-alkyl, aryl or O-aryl groups, optionally substituted with halogen, O—R4, N—R5R6, R7; R4, R5, R6, R7 represent independently the same or different alkyl or aryl groups, optionally substituted with halogen, O-alkyl; and Cl.sup.− represent counter ions including chloride, bromide, iodide, acetate, or gluconate.

4. The biocide solution according to claim 1, comprising a preservation-effective amount of a compound for a pharmaceutical composition.

5. The biocide solution according to claim 2, comprising a preservation-effective amount of a compound for a pharmaceutical composition.

6. The biocide solution according to claim 1, comprising a disinfecting-effective amount of a compound for a lens care composition.

7. The biocide solution according to claim 2, comprising a disinfecting-effective amount of a compound for a lens care composition.

8. The biocide solution of claim 2, wherein the composition may contain one or more additional antimicrobial agent, for example but not limited to, polyhexamethylene biguanide polymers (“PHMB”), polyquaternium-1, myristamidopropyl dimethylamine (Aldox), and the amino biguanides.

11. The biocide solution of claim 2, wherein the concentration of the compound in the ophthalmic solution ranges from 0.0001 to 5.0 w/v %.

12. The biocide solution according to claim 1 comprising a preservation-effective amount of a compound for a mouth wash composition.

13. The biocide solution according to claim 2 comprising a preservation-effective amount of a compound for a mouth wash composition.

14. A method for preparation of a compound according to claim 2 by a process of: a) condensation of sodium dicyanamide and a trifunctional primary amine, b) reaction with anilines hydrochloride, wherein trifunctional primary amine is selected from the groups consisting of propane-1,2,3-triamine, pentane-1,3,5-triamine, N.sup.1,N.sup.1-bis(2-aminoethyl)-ethane-1,2-daiamine, N.sup.2,N.sup.4,N.sup.6-tris(6-aminohexyl)-1,3,5-triazine-2,4,6-triamine, N.sup.2,N.sup.4,N.sup.6-tris(6-aminopropyl)-1,3,5-triazine-2,4,6-triamine, N.sup.2,N.sup.4,N.sup.6-tris(6-aminobutyl)-1,3,5-triazine-2,4,6-triamine, N.sup.2,N.sup.4,N.sup.6-tris(6-aminoheptyl)-1,3,5-triazine-2,4,6-triamine, N.sup.2,N.sup.4,N.sup.6-tris(6-aminopentyl)-1,3,5-triazine-2,4,6-triamine.

15. A method for preparation of a compound according to claim 2 by a process of: a) condensation of sodium dicyanamide and anilines hydrochloride, b) reaction with a trifunctional primary amine and acid, wherein trifunctional primary amine is selected from the groups consisting of propane-1,2,3-triamine, pentane-1,3,5-triamine, N.sup.1,N.sup.1-bis(2-aminoethyl)-ethane-1,2-daiamine, N.sup.2,N.sup.4,N.sup.6-tris(6-aminohexyl)-1,3,5-triazine-2,4,6-triamine, N.sup.2,N.sup.4,N.sup.6-tris(6-aminopropyl)-1,3,5-triazine-2,4,6-triamine, N.sup.2,N.sup.4,N.sup.6-tris(6-aminobutyl)-1,3,5-triazine-2,4,6-triamine, N.sup.2,N.sup.4,N.sup.6-tris(6-aminoheptyl)-1,3,5-triazine-2,4,6-triamine, N.sup.2,N.sup.4,N.sup.6-tris(6-aminopentyl)-1,3,5-triazine-2,4,6-triamine.

16. The biocide solution according to claim 2 comprising a compound including at least one of the following chemicals: ##STR00014##

Description

[0030] The following schemes further illustrate certain embodiments of the invention. These examples are provided to aid in the understanding of the invention and are not to be construed as limitations thereof.

##STR00006##

##STR00007##

[0031] The compounds of the formula 1, 2, 3, and 4 were prepared using synthetic methods disclosed in the prior art.

[0032] Compound 1 (USD-18). Reaction of sodium dicyanamide with N.sup.1,N.sup.1-bis(2-aminoethyl)ethane-1,2-diamine (tri(2-aminoethyl)amine) and concentrated HCl in alcohol at 80-130° C. for 8-24 h gave the intermediate, tris((N.sup.3-cyano-N.sup.1-guanidino)ethyl)amine after purification. LCMS 248 (M+1). Reaction of tris((N.sup.3-cyano-N.sup.1-guanidino)ethyl)amine and 4-chloroaniline hydrochloride in alcohol at 80-150° C. for 2-8 h gave a white precipitate that was purified to give the desired compound as a white solid. NMR (CD.sub.3OD/D.sub.2O)□□7.10 (d, J=6 Hz, 6H), 7.01 (d, J=6 Hz, 6H), 4.91 (bs, 3H), 2.73 (bs, 6H), 2.08 (bs, 6H). □

[0033] Compound 2 (USD-19). Using the same procedure above and 4-trifluoromethylaniline hydrochloride the desired compound 2 was prepared as an off-white solid. NMR (DMSO/D2O) d 7.41 (bd, 6H), 7.30 (d, J=6 Hz, 6H), 3.25 (bs, 6H), 2.55 (bs, 6H).

[0034] Compound 3 (USD-39). Using the same procedure as in the preparation of Compound 1 and N.sup.1, N.sup.1-bis(3-aminopropyl)propane-1,3-diamine the desired Compound 3 was prepared as an off-white solid.

[0035] Compound 4 (USD-40). Using the same procedure above and 4-trifluoromethylaniline hydrochloride the desired Compound 4 was prepared as an off-white solid.

[0036] Compound 5 (USD-42). Using the same procedure as in the preparation of Compound 1 and N.sup.1, N.sup.1-bis(2-aminoethyl)propane-1,3-diamine the desired Compound 5 was prepared as an off-white solid.

[0037] Compound 6 (USD-45). Using the same procedure above and 4-trifluoromethylaniline hydrochloride the desired Compound 6 was prepared as an off-white solid.

##STR00008##

[0038] Compound 7 (USD-20). This is the reference compound (chlorhexidine dihydrochloride, CHX) and was obtained from Sigma-Aldrich.

##STR00009##

[0039] The antibacterial effectiveness testing was run against 7 strains of bacteria using the following protocol.

[0040] Protocol: In 96 well polystyrene plates, compounds (USD-18, 19, 39, 40, 42, 45, and 20) are added using serial dilution method (0.19 mg/mL-100 mg/L) in brain heart infusion (BHI) broth media (containing acetic acid/BSA or not containing acetic acid/BSA*). Bacteria (either E. coli or P. aeruginosa or S. aureus or S. marcenes or K. pneumonia or A. baumanni or C. albicans) are added to all well except the control and incubated at 37° C. for 24 h. The absorbance was read at 600 nm.

[0041] MIC90 was calculated as the concentration at which ˜90% growth inhibition is noticed. N=4 replicates for each compound and bacteria.

TABLE-US-00001 MIC.sub.90 MIC.sub.90 MIC MIC MIC MIC MIC (P. aeruginosa, (E. coli, (S. aeureus, (S. marcenes, (K. pneumonia, (A. baumanni- (C. albicans, Compound μg/ Beginning ATCC-9027) ATCC-8739) ATCC 6538) ATCC-21639) ATCC-18804) ATCC-19606) ATCC1-0231) ID ML concentration in μg/mL in μg/mL in μg/mL in μg/mL in μg/mL in μg/mL in μg/mL USD 18* 1000 suspension 6.25 3.12 0.78 3.12 3.12 USD 19* 1000 suspension 12.5 12.5 3.12 3.12 3.12 USD 20* 1000 suspension 25 0.78 0.78 6.25 25 25 USD 18 1000 suspension 0.76 3.15 0.76 50 12.5 6.25 6.25 USD 19 1000 suspension 3.15 315 1.5 100 25 1.5 6.25 USD 18 1000 in DMSO/ 0.76 6.25 0.76 12.5 6.25 0.39 3.12 Water USD 20 1000 in DMSO/ 1.5 1.5 0.76 3.25 3.12 0.39 12.5 Water USD 39 1000 soluble in 3.125 50 12.5 water USD 40 1000 soluble in 3.125 12.5 12.5 water USD 42 1000 soluble in 3.125 12.5 6.25 water USD 45 1000 soluble in 6.25 6.25 6.25 water