MXPA01006160A - Amido polybiguanides and the use thereof as antimicrobial agents - Google Patents

Abstract

Amido polybiguanides and their use as antimicrobial agents in pharmaceutical compositions are disclosed. A method of synthesis of amido polybiguanides is also disclosed. The amido polybiguanides are useful in the preservation of pharmaceutical compositions, particulary ophthalmic and otic pharmaceutical compositions and compositions for treating contact lenses. The compounds are especially useful for disinfecting contact lenses.

Description

AM.PQPOLIBIGUANIPA AND THE USE OF THEM AS AGENTS \ ANTIMICROBIALS "? BACKGROUND OF THE INVENTION The present invention relates to novel polymeric biguanides having potent antimicrobial activity and little, if any, toxicity relative to human tissues. The amidopolybiguanides described herein have many industrial applications, but are especially useful as antimicrobial preservatives in pharmaceutical composns. The invention particularly relates to the use of these compounds in composns and methods for disinfecting contact lenses, and to the preservation of different types of ophthalmic and optical pharmaceutical composns.

/ Contact lenses are exposed to a broad spectrum of microbes during normal use and get dirty relatively quickly. Therefore, routine cleaning and disinfection of the lenses is required. Although the frequency of cleaning and disinfection may vary slightly between different types of lenses and regulations for lens care, daily cleaning and disinfection is usually required. The lack of cleaning and disinfection of the lenses can properly lead to a variety of problems ranging from simple discomfort when the lenses are used to serious eye infections. Eye infections caused by particularly virulent microbes, such as Pseudomonas aeruginosa, can lead to the loss of the infected eye (s) if it is left untreated, or if it is allowed to reach an advanced stage before it is start the treatment. Therefore, it is extremely important that patients disinfect their contact lenses according to the treatment prescribed by their optometrist or ophthalmologist. Unfortunately, patients often do not follow the prescribed treatments. Many patients find the treatments difficult to understand and / or complicated, and as a result they do not comply with one or more aspects of the treatment. Other patients may have a negative experience with the treatment, such as ocular discomfort attributable to the disinfecting agent, and as a result they do not routinely disinfect their lenses or otherwise deviate from the prescribed treatment. In any case, the risk of eye infections becomes worse. Despite the availability of different types of contact lens disinfection systems, such as heat, hydrogen peroxide, and other chemical agents, there is still a need for improved systems which: 1) are easy to use, 2) are active potent antimicrobial, and 3) are non-toxic (ie, do not cause eye irritation as a result of binding to the lens material). Conventional contact lens cleaners with potent antimicrobial activity also have rather high toxicity. Therefore, there is a particular need in the fields of disinfection of contact lenses and preservation of ophthalmic composn, of safe and effective chemical agents with high antimicrobial activity and low toxicity. The use of polymeric biguanide compounds as disinfecting agents is known. The commercially available polybiguanides are hexamethylene biguanide polymers having end groups consisting of a cyanoguanidine group and an amino group, respectively. The widely used polybiguanide Cosmocil CQ (polyhexamethylene biguanide or "PHMB") has strong antimicrobial activity, but also high toxicity. A primary objective of the present invention is to provide polymeric biguanides that retain the antimicrobial activity compared to PHMB, but which are less toxic to human tissue than PHMB. As explained below, this objective has been achieved by means of a unique modification of the terminal amino groups of PHMB. The present invention relates to the satisfaction of the aforementioned needs and objectives.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to polybiguanides having an amido moiety as the first terminal group and a cyanoguanidine moiety as the second terminal moiety. These compounds have antimicrobial activity compared to PHMB, but are generally less toxic than PHMB. The invention also relates to contact lens disinfectant compositions which contain the subject compounds, and to different ophthalmic compositions (eg, pharmaceuticals, artificial tears and resting drops) and other types of pharmaceutical compositions containing the compounds for the purposes of preserve the compositions against microbial contamination. Modification of the amino moiety of known polybiguanides to an amido moiety containing the substituents described herein results in good antimicrobial activity and reduced toxicity over the prior art compounds. In addition, the addition of specific substituents to the PHMB polymer changes its physicochemical and biochemical properties to provide a compound whose toxicity profile is lower than that of PHMB, and maintains the antimicrobial activity of PHMB. As discussed above, Cosmocil CQ is a widely used, commercially available polyhexamethylene biguanide biguanide ("PHMB") disinfectant containing a terminal amino group. PHMB has strong antimicrobial activity, but instead, high toxicity. A key difference between the compounds of the present invention and conventional PHMB is the modification of the terminal amino group of PHMB to form an amido group. This modification has resulted in the production of a new class of compounds that have properties that are superior to those of PHMB. This invention also involves a modification of the PHMB polymer to include other substituents that change their physical, chemical and biochemical properties to provide compounds whose toxicity profiles are inferior to those of PHMB, while maintaining the potent antimicrobial activity of PHMB.

DESCRIPTION OF THE PREFERRED MODALITY The compounds of the present invention are polybiguanides in which the first terminal group is an amido moiety and the second terminal moiety is a cyanoguanidine moiety. The compounds have the following formula: RC (= 0) NH-X- [NHC (= NH) NHC (= NH) NH-X-] nNHC (= NH) NHCN (I) wherein: n is an integer in the scale from 1 to 100; X is alkyl, saturated or unsaturated cycloalkyl, alkyl substituted with cycloalkyl, aryl, or aralkyl, with the proviso that the X groups contain from 1 to 40 carbon atoms (Ci to C40) and are substituted or unsubstituted with any number of N, O, S, P, B, F, Cl, Br, or I; and R is a saturated or unsaturated alkyl (C. to C50), cycloalkyl (C3 to Cso), alkyl substituted with cycloalkyl, polyethylene oxide having a molecular weight of 50 to 10,000 (MW 50-10,000), polypropylene oxide which has a molecular weight of 50 to 10,000 (MW 50-10,000), any combination of the above groups, unsubstituted aralkyl, aralkyl substituted with any number of N, O, S, P, B, F, Cl, Br, or I , unsubstituted aryl, or aryl substituted with any number of N, O, S, P, B, F, Cl, Br, or I.

The substituent R in compounds of formula I optionally includes amide, urea or other functional groups of covalent bond. As used herein, the term "alkyl" includes straight or branched chain hydrocarbon groups. The alkyl groups may be substituted with other groups, such as halogen, hydroxyl or alkoxy. Preferred compounds are those in which n is 4 to 16, X is alkyl or aralkyl and R is polyethylene oxide (P.M. 100 to 2,000) or alkyl ether of polyethylene oxide (P.M. 100 to 2,000). The use of polyethylene oxide as the R group is preferred because this substituent has been found particularly effective in reducing the toxicity of biguanides. The following compounds are particularly preferred: Number of n X R compound Compound number 2 is the most preferred. The compounds of the present invention can be prepared by the method illustrated in Scheme I below: SCHEME 1 In general, the synthesis of the amidobiguanides of the present invention is carried out by reacting the terminal amino group of a polybiguanide with an N-hydroxysuccinimide ester of the desired substituent, R, in the presence of a sterically hindered base, preferably diisopropylethylamine, in a suitable solvent, preferably DMSO, at room temperature for 8-20 hours. The compounds of the present invention wherein R is a polyethylene oxide, can be prepared by the method illustrated below in Scheme 2: SCHEME 2 Reaction scheme for succinimidylic polyethylene oxide succinate (P.M. 550) (compound 4) CH OH thionyl chloride asium t1 »CH3. Pyridine ot phthalamide, CHCl3 reflux Compound 5 CH NHj hydrazine CH3 EtOH, reflux X-io II overnight Compound 7 tA or Compound 6 succinic anhydride diisopropylethylamine chloroform, reflux 4hrs Synthesis of compound 5 50 ml of a chloroform solution of 11.0 g (0.02 mole) of poly (ethylene glycol) monomethyl ether (polyethylene oxide, PEO) PM 550 (Aldrich lot # 05022ET) and 1.6 g (0.02 mole) of pyridine was added dropwise under an N2 atmosphere to 75 ml of chloroform solution of 3.09 g (0.26 mole) of thionyl chloride. After addition, the reaction mixture was heated to reflux (70 ° C) under constant stirring for 2.5 hours. The organic layer was washed with 3 x 50 mL of aqueous sodium chloride and sodium carbonate followed by 2 x 60 mL of aqueous sodium chloride, dried (sodium sulfate), filtered and concentrated in vacuo to obtain 11.14 g (0.0196). moles, 98.0%) of compound 5. The structure was confirmed with NMR by observing the change in chemical shift from a methylene adjacent to the terminal hydroxyl group (d 3.69, t, 2H) to a methylene adjacent to the terminal chlorine group (d 3.77, t, 2H).

Synthesis of compound 6 2.85 g (0.005 mole) of compound 5 and 1.21 g (0.0065 mole) of potassium phthalimide were mixed in 10 ml of dimethylformamide (DMF) and heated at 120 ° C under constant stirring for 4 hours. The DMF was removed in vacuo and the remaining residue was dissolved in 20 ml of chloroform, filtered and concentrated in vacuo to yield 3.4 g (0.005 mol, 100%) of compound 6. The structure was confirmed with NMR by observing the appearance of peaks. of aromatic phthalimide (d 7.70 and 7.85, m, 4H) and change in chemical displacement of a methylene adjacent to the terminal chlorine group (d 3.77, t, 2H) to a methylene adjacent to the terminal phthalamide group (d 3.90, t, 2H) .

Synthesis of compound 7 3.4 g (0.005 mole) of compound 6 and 5 g (0.011 mole) of hydrazine (35% w / w in water) were dissolved in 139 ml of ethanol and heated to reflux (80 ° C) overnight . The solution produced copious precipitation which was filtered after heating. The residue was dissolved in ethyl acetate and refrigerated overnight to induce precipitation of phthalhydrazide. The solution was filtered and redissolved in chloroform and refrigerated overnight. The solution was then filtered and concentrated in vacuo to yield 2.08 g (0.0038 mol, 75.6%) of compound 7. The structure was confirmed with NMR by observing the disappearance of phthalimide peaks and appearance of a methylene adjacent to the terminal primary amine group ( d 2.86, t, 2H).

Synthesis of compound 8 7.75 g (0.014 mole) of compound 7, 1.75 g (0.0175 mole) of succinic anhydride and 2.59 g (0.02 mole) of N, N-diisopropylethylamine were dissolved in 100 ml of chloroform and heated to reflux (70 ° C). C) for four hours. The reaction mixture was then diluted to 150 ml and washed with 3 × 50 ml of aqueous sodium chloride and 1 N HCl followed by 2 × 50 ml of aqueous sodium chloride. The solution was then dried (sodium sulfate), filtered and concentrated in vacuo to yield 7.11 g (0.011 mol, 78.2%) of compound 8. The structure was confirmed with NMR by observing the appearance of succinylmethylene groups (d 2.55 and 2.65, m, 4H) and change in chemical shift from a methylene adjacent to an amine (d 2.86, t, 2H) to a methylene adjacent to an amide (d 3.44, t, 2H).

Synthesis of compound 4 2.85 g (0.0044 mol) of compound 8 and 0.51 g (0.0044 mol) of N-hydroxysuccinimide were dissolved in 40 ml of tetrahydrofuran and stirred for 20 minutes. Then 0.91 g (0.0044 mol) of 1,3-dicyclohexylcarbodiimide (DCC) was added and the reaction mixture was stirred overnight. 8 drops of glacial acetic acid were added to convert the DCC residue to DCU (dicyclohexylurea). This was monitored by IR observing the disappearance of the diimide peak (2100 cm "1) .The mixture was then concentrated in vacuo, dissolved in ethyl acetate (40 mL) and cooled to induce DCU crystallization.The solution was then filtered and concentrated in vacuo to yield 3.28 g (0.0044 mole, 100%) of succinimylsilycinazine monomethyl ether of PEO PM 550. The product was confirmed with NMR by observing the appearance of the N-hydroxysuccinimide methylene groups (d 2.84, s, 4H) and change in chemical shift of succinylmethylene groups (d 2.55 and 2.65, m, 4H) to succinimylsilycinamidamethylene groups (d 2.99 and 2.61, t, 4H) The compounds of the present invention display a strong profile of antimicrobial activity, as discussed above, which is similar to unmodified polyhexamethylene biguanide ("PHMB"), but has significantly less toxicity than unmodified PHMB The compounds discussed herein may be used independently. vidual or in combination with other disinfectants or preservatives. The amount of each compound used will depend on the purpose of use, for example, disinfection of contact lenses or preservation of pharmaceutical products, and the absence or inclusion of other antimicrobial agents. The concentration determined to be necessary for the aforementioned purposes can be functionally described as "an effective amount to disinfect" and "an effective amount to conserve", or "effective amounts of microbiocidal form", or variations thereof. The concentrations used for disinfection will generally be in the range of about 0.00001 to about 0.01% by weight based on the total weight of the composition ("% by weight"). The concentrations used for preservation will generally be in the range of about 0.00001 to about 0.001% by weight. The compositions of the current inventions can be aqueous or non-aqueous, but will generally be aqueous. As will be appreciated by those skilled in the art, the compositions may contain a wide variety of ingredients, such as tonicity agents (e.g., sodium chloride or mannitol), surfactants (e.g., polyvinylpyrrolidone and polyoxyethylene / polyoxypropylene copolymers). , viscosity adjusting agents (eg, hydroxypropylmethyl cellulose and other cellulose derivatives) and pH regulating agents (eg, borates, citrates, phosphates and carbonates). The ability of the compounds of the present invention to retain their antimicrobial activity in the presence of such agents is an important advantage of the present invention. The pharmaceutical compositions of the present invention will be formulated to be compatible with human tissues that will be treated with the compositions (e.g., eye or ear tissues), or contact lenses that will be treated. Formulations that meet these basic requirements are referred to herein as "pharmaceutically acceptable carriers" for the compounds of the present invention or, in the case of compositions for treating the eye or contact lenses, "ophthalmically acceptable carriers". As will be apparent to those skilled in the art, ophthalmic compositions that have the purpose of direct application to the eye will be formulated to have a pH and tonicity which are compatible with the eye. This will usually require a pH regulator to maintain the pH of the composition at or near physiological pH (i.e., 7.4) and may require a tonicity agent to bring the osmolality of the composition to a level at or about 280 to 320 milliosmoles per kilogram of water ("mOsm / kg) The formulation of compositions for disinfecting and / or cleaning contact lenses will involve similar considerations, as well as considerations regarding the physical effect of the compositions on contact lens materials and the potential of the lens to bind or absorb the components of the composition. The disinfecting compositions for contact lenses of the present invention will preferably be formulated as aqueous solutions, but can also be formulated as non-aqueous solutions, as well as suspensions, gels, etc. The compositions may contain a variety of tonicity agents, surfactants, viscosity adjusting agents, and pH regulating agents, as described above. The compositions described above can be used to disinfect contact lenses according to procedures known to those skilled in the art. More specifically, the lenses will first be removed from the eyes of the patients, and then immersed in the compositions for a sufficient time to disinfect the lenses. Immersion will typically be done by immersing the lenses in a solution overnight (ie, approximately 6 to 8 hours). The lenses will then be rinsed and placed in the eye. Before immersion in the disinfectant compositions, preferably the lenses will also be cleaned and rinsed. The compositions and methods of the present invention can be used in conjunction with different types of contact lenses, including both generally classified as "hard" lenses, and lenses generally classified as "soft" lenses. The compounds of the present invention can also be included in different types of pharmaceutical compositions as preservatives, to avoid microbial contamination of the compositions. The types of compositions which can be preserved by the compounds of the present invention include: ophthalmic pharmaceutical compositions, such as topical compositions used in the treatment of glaucoma, infections, allergies or inflammation; otic pharmaceutical compositions, such as topical compositions gradually introduced into the ear for treatment of inflammation or infection; compositions for treating contact lenses, such as disinfectant solutions, cleaning products and products for improving the ocular comfort of patients wearing contact lenses; other types of ophthalmic compositions, such as ocular lubricant products, artificial tears, astringents, etc; dermatological compositions, such as anti-inflammatory compositions, as well as shampoos and other cosmetic compositions; and other different types of pharmaceutical compositions. The present invention is not limited with respect to the types of ophthalmic compositions in which the compounds of the present invention can be used as preservatives. The following examples are presented to further illustrate different aspects of the present invention.

EXAMPLE 1 The preferred amidobiguanide of the present invention, identified above as compound 2, can be prepared as follows: 0.50 g (0.35 mmol) of solid Cosmocil CQ (polyhexamethylenebiguanide, 5.5 repetition units on average) obtained by lyophilization of an aqueous solution to the 20% w / w and 0.09 g (0.70 mmol) of diisopropylethylamine were dissolved in 2.5 ml of dimethylsulfoxide (DMSO) and stirred at room temperature for 30 minutes under an argon atmosphere. Then 0.39 g (0.53 mmoles) of succinimidylsuccinamidamonomethyl ether of PEO PM 550 (compound 4) was added and the reaction mixture was stirred overnight. The DMSO was removed in vacuo and the remaining residue was dissolved in methanol (1.0 ml), acidified with HCl and precipitated with acetone (40 ml). The acetone was decanted and the precipitate dissolved in 1 ml of water and precipitated with acetone (40 ml). Then the precipitate was dissolved in water (5 ml) and concentrated in vacuo to remove any remaining acetone. Then the precipitate was dissolved in 5 ml of water and lyophilized to obtain 0.39 g of compound 2 (12 repeating units of biguanide). NMR and elemental analysis confirmed the structure. The number of repeating units was determined with NMR by comparison of integration peaks of the methylene groups adjacent to biguanide units and to the methylene groups of polyethylene oxide. Elemental analysis helped confirm this discovery. Elemental analysis calculated for Ci33H3a or 6eCl24? I4 + 5 H2O (MW 3989.226): C, 40.04; H, 7.83; N 23.17; Cl, 21.33 Found: C, 39.96; H, 7.93; N, 23.09; Cl, 20.60. 1 H NMR (200 MHz, D 3 O): d 3.6 (broad peak, 48H, OCÜQHsO), 3.34 (s, 3H, CH3O), 3.3 (t, 48H, 6H, CH2NHC (= NH) NHCN and CH2NH 1.6 (broad peak, 48H, NHC (= NH) NHCH2CH2), 1.37 (broad peak, 48H, NHC (= NH) NHCH2CH2CH2).

EXAMPLE 2 The amidobiguanide of the present invention identified above as compound number 1 can be prepared as follows: 0.50 g (0.35 mmoles) of solid Cosmocil CQ and 0.18 g of N, N-diisopropylethylamine were dissolved in 3.5 ml of DMSO and stirred for 45 minutes. Then 0.14 g of N-hydroxysuccinimide ester of myristic acid (synthesized by coupling of myristic acid and N-hydroxysuccinimide in the presence of DCC) was added and the reaction mixture was stirred overnight. Then it was precipitated with acetone (50 ml). The acetone was decanted and the precipitate was dissolved in 2 ml of water and precipitated with acetone (40 ml) and the acetone was decanted. This procedure of dissolving in water, precipitation with acetone and decanting the acetone layer was repeated twice more. Then the precipitate was dissolved in 5 ml of water and concentrated in vacuo to remove the remaining acetone. It was then redissolved in water (5 ml) and dried to yield 0.28 g (0.079 mmol, 45%) of compound 1 (14 units of biguanide). The structure was confirmed by NMR and elemental analysis. The molecular weight was determined with NMR by comparing the integration peaks corresponding to the methylene groups adjacent to the biguanides and to the terminal methyl group in the alkyl chain substituent. This was confirmed with elemental analysis. Elemental analysis calculated for Ci34H295N75Cl? 0 + 4.5 H2O (PM 3550.72): C, 45.33; H, 8.63; N 29.58; Cl, 13.98 Found: C, 45.30; H, 8.76; N, 29.13; Cl, 14.23. 1 H NMR (200 MHz, D 20): d 3.14 (broad t, 56 H, CH 2 NHC (= NH) NHC (= NH) NHCH 2), 2.2 (t, 2 H, CH 2 C (= 0) NH), 1.51 (broad peak , 56H, NHC (= NH) NHCH2CH2), 1.31 (broad peak 56H, NHC (= NH) NHCH2CH2CH2), 1.21 (broad peak, 22H, CH3 (CH2) 11), 0.8 (t, 3H, CH3 (CH2) n ).

EXAMPLE 3 The amidobiguanide of the present invention identified above as compound number 3 can be prepared as follows: 0.50 g (0.00035 mole) of solid Cosmocil CQ and 0.18 g (0.0014 mole) of diisopropylethylamine were dissolved in 2.5 ml of DMSO and stirred for 45 minutes. Then 0.07 g (0.00045 mole) of N-hydroxysuccinimide acetic acid ester was added and the reaction mixture was stirred overnight. Then the mixture was precipitated with acetone and the acetone layer was decanted. Then the procedure of dissolving the precipitate in 1 ml of water, precipitate with acetone and then decant the acetone was repeated three times. The precipitate was then dissolved in water, concentrated in vacuo, redissolved in water and lyophilized to yield 0.14 g (0.000049 moles, 25%) of compound 3 (12 biguanide repeating units). The structure was confirmed by NMR and elemental analysis. The number of repeat units was determined with NMR by comparing the integration peaks of the terminal methyl group with the methylene groups adjacent to the biguanide. Elemental analysis calculated for CIOSH? SSNTSCI ^ O (PM 2861.92): c, 44.49; H, 8.28; N 31.81; Cl, 14.87 Found: C, 44.96; H, 8.34; N, 31.17; Cl, 14.60. 1 H NMR (200 MHz, D 20): d 3.15 (broad t, 48 H, CH 2 NHC (= NH) NHC (= NH) NHCH 2), 1.93 (s, 3 H, CH 3 C (= 0) NH), 1.52 (broad peak, 48 H , NHC (= NH) NHCH2CH2), 1.31 (broad peak 48H, NHC (= NH) NHCH2CH2CH2).

EXAMPLE 4 The following formulation is provided to further illustrate the compositions of the present invention, particularly compositions used to disinfect contact lenses.

Quantity ("/ O by weight). Compound composition 0.00001 to 0.01 Boric acid 0.58 Sodium borate 0.18 Sodium chloride 0.49 Sodium edetate 0.05 NaOH / HCl qs pH 7.0 In this formulation, the term" compound "refers to any of the compounds of the present invention, particularly those of the formula (I) above.

EXAMPLE 5 The antimicrobial activity of the compounds of the present invention is demonstrated by the microbiological data provided in the table below. Three compounds of the present invention (ie, compound No. 1, compound No. 2 and compound No. 3) were tested at concentrations of 0.0005% by weight. The compounds were tested using water or the formulation of Example 4 as the carrier for the compounds. (The formulation of Example 4 is referred to in the table below as "FID 84509"). After the box, a description of the testing procedures is provided. a The underlined number indicates that no survivors were recovered (< 10 CFU / mL). The bacteria Serratia marcescens ATCC 13880 and Staphylococcus aureus ATCC 6538 were grown in inclined tubes of agar for soybean casein digestion (SCDA). The yeast Candida albicans ATCC 10231 was grown in inclined tubes of Sabouraud Dextrose Agar. Surface growth of the three microorganisms was cultured with phosphate buffered saline containing Poiisorbate 80. The microbial suspensions were spectrophotometrically adjusted to a concentration of approximately 1.0 x 108 colony forming units / mL (CFU / mL). The test compounds were separated into target concentrations in selected vehicles. Ten mL of test solution was inoculated with 0.1 mL of the appropriate microbial suspension so that the test solution contained approximately 1.0 x 10 6 CFU / mL. The tubes were thoroughly mixed and kept at room temperature during the test. At six and 24 hours after the inoculation of test solution, an aliquot of 1.0 mL of each test sample was transferred for each attack organism to 9.0 mL of Dey Engley Neutralizing Broth preforms. The samples were serially diluted in the neutralizing broth and flow plates were prepared from suitable dilutions with neutralizers containing SCDA. Petri dishes were incubated for 48-72 hours and the number of survivors visible as separate colony forming units was determined according to standard microbiological methods. The invention has been described as reference to certain preferred embodiments; however, it will be understood that it can be modalized in other forms or specific variations of the same without departing from its spirit or essential characteristics. Therefore, the modalities described above are considered illustrative in all respects and not restrictive, indicating the scope of the invention through the appended claims, rather than the foregoing description.

Claims (9)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound comprising an amidopolyguiguanide wherein a first terminal group is an amido moiety and a second terminal moiety is a cyanoguanidine moiety.

2.- A compound of the following formula: RC (= 0) NH-X- [NHC (= NH) NHC (= NH) NH-X-] nNHC (= NH) NHCN where: n is an integer in the scale from 1 to 100; X is alkyl, saturated or unsaturated cycloalkyl, alkyl substituted with cycloalkyl, aryl, or aralkyl, with the proviso that the X groups contain from 1 to 40 carbon atoms (Ci to C40) and are substituted or unsubstituted with any number of N, O, S, P, B, F, Cl, Br, or I; and R is a saturated or unsaturated alkyl (C1 to C50), cycloalkyl (C3 to C50), alkyl substituted with cycloalkyl, polyethylene oxide having a molecular weight of 50 to 10,000 (MW 50-10,000), polypropylene oxide having a molecular weight of 50 to 10,000 (MW 50-10,000), any combination of the above groups, unsubstituted aralkyl, aralkyl substituted with any number of N, O, S, P, B, F, Cl, Br, or I, unsubstituted aryl, or aryl substituted with any number of N, O, S, P, B, F, Cl, Br, or I, optionally including one or more amide, urea or other functional groups of covalent bond.

3. - The compound according to claim 2, further characterized in that R is polyethylene oxide having a molecular weight of 50 to 10,000.

4. A pharmaceutical composition comprising an effective microbiocidal amount of the compound of claim 2.

5. An ophthalmic composition for disinfecting contact lenses, comprising: a compound of the following formula in an amount effective to disinfect lenses of contact: RC (= O) NH-X- [NHC (= NH) NHC (= NH) NH-X-] nNHC (= NH) NHCN where: n is an integer on the scale from 1 to 100; X is alkyl, saturated or unsaturated cycloalkyl, alkyl substituted with cycloalkyl, aryl, or aralkyl, with the proviso that the X groups contain from 1 to 40 carbon atoms (Ci to C40) and are substituted or unsubstituted with any number of N, O, S, P, B, F, Cl, Br, or I; and R is a saturated or unsaturated alkyl (C. to C50), cycloalkyl (C3 to C50), alkyl substituted with cycloalkyl, polyethylene oxide having a molecular weight of 50 to 10,000, polypropylene oxide having a molecular weight of 50. to 10,000, any combination of the above groups, unsubstituted aralkyl, aralkyl substituted with any number of N, O, S, P, B, F, Cl, Br, or I, unsubstituted aryl, or aryl substituted with any number of N, O, S, P, B, F, Cl, Br, or I, optionally including one or more amide, urea or other functional groups of covalent bond; and an ophthalmically acceptable vehicle for said compound.

6. - A method for disinfecting a contact lens which comprises immersing the lens in the composition of claim 5 for a sufficient time to disinfect the lens.

7. A method for protecting a pharmaceutical composition from microbial contamination which comprises including in the composition an effective amount of preservative of a compound of the following formula: RC (= O) NH-X- [NHC (= NH) NHC ( = NH) NH-X-] nNHC (= NH) NHCN where: n is an integer on the scale from 1 to 100; X is alkyl, saturated or unsaturated cycloalkyl, alkyl substituted with cycloalkyl, aryl, or aralkyl, with the proviso that the X groups contain from 1 to 40 carbon atoms (C. to C ") and are substituted or unsubstituted with any number of N, O, S, P, B, F, Cl, Br, or I; and R is a saturated or unsaturated alkyl (Ci to C50), cycloalkyl (C3 to C50), alkyl substituted with cycloalkyl, polyethylene oxide having a molecular weight of 50 to 10,000 (MW 50-10,000), polypropylene oxide having a molecular weight of 50 to 10,000 (MW 50-10,000), any combination of the above groups, unsubstituted aralkyl, aralkyl substituted with any number of N, O, S, P, B, F, Cl, Br, or I, unsubstituted aryl, or aryl substituted with any number of N, O, S, P, B, F, Cl, Br, or I, optionally including one or more amide, urea or other functional groups of covalent bond.

8. The method according to claim 7, further characterized in that the composition is an ophthalmic pharmaceutical composition.

9. - The method according to claim 7, further characterized in that the composition is an otic pharmaceutical composition.