MXPA00006038A - Aminobiguanides and the use thereof to disinfect contact lenses and preserve pharmaceutical compositions - Google Patents

Abstract

Aminobiguanides and the use of same as antimicrobial agents in pharmaceutical compositions are disclosed. The aminobiguanides are useful in the preservation of pharmaceutical compositions, particularly ophthalmic pharmaceutical compositions and compositions for treating contact lenses. The compounds are especially useful for disinfecting contact lenses.

Description

AMINOBIGUANIDAS AND THE USE OF THEM TO SANITIZE CONTACT LENSES AND PRESERVE COMPOSITIONS PHARMACEUTICALS BACKGROUND OF THE INVENTION The present invention relates to aminobiguanides with antimicrobial activity, and to the use of these aminobiguanides in pharmaceutical compositions. Specifically, the invention relates to the use of certain aminobiguanides in compositions and methods for disinfecting contact lenses, and to the use of these compounds to preserve various types of pharmaceutical compositions and to prevent these compositions from being contaminated by microbes, particularly in the case of compositions. ophthalmic and otic pharmaceuticals. Contact lenses are exposed to a broad spectrum of microbes during normal use and become relatively dirty. This type of lens therefore requires routine washing and disinfection. The frequency of this cleaning and disinfection depends to a certain extent on the different types of lenses and their specific care requirements, but normally they should be washed and disinfected once a day. Failure to do so, a dirty lens could cause a series of problems ranging from simple discomfort to the use of lenses to serious eye infections. Eye infections caused by particularly virulent microbes, such as Pseudomonas aeruginosa, can cause the loss of the infected eye or eyes if they are not treated or if they are allowed to reach an advanced stage before starting treatment. Therefore, it is extremely important that patients disinfect their contact lenses in accordance with the regimen prescribed by their optometrist or ophthalmologist. Unfortunately, patients often do not follow the doctor's specifications to the letter. Many patients consider these specifications difficult to understand and / or complicated and consequently do not comply with one or more aspects of them. Other patients may have some negative experience with these specifications, such as some eye discomfort that can be attributed to the disinfecting agent, and as a result do not disinfect their lenses on a routine basis or do not follow the doctor's specifications at face value. In either case, the risk of developing an eye infection increases. Despite the availability of several types of systems to disinfect contact lenses, such as the application of heat, hydrogen peroxide, and other chemical agents, the need to improve these systems prevails so that: 1) they are easy to use, 2) have an intense antimicrobial activity, and 3) that are not toxic (that is, they do not cause eye irritation as a result of their adherence to the lens material). There is also a need for chemical disinfecting agents that retain their antimicrobial activity in the presence of salts (e.g., sodium chloride) and other components of compositions used to maintain contact lenses. For example, the patent of the U.S.A. No. 4,438.01 1 issued to Howes, indicates that there are ionic species such as chloride that inhibit the antimicrobial activity of biguanide chlorhexidine, and that the concentration of these ionic species must therefore be reduced in order to maintain the proper antimicrobial activity. to effectively disinfect contact lenses. There is also a need to find better means to prevent the pharmaceutical compositions from being contaminated by microbes. This need is particularly frequent in the fields of ophthalmic and otic compositions. The antimicrobial agents used to preserve aqueous ophthalmic and otic compositions should be effective in preventing microbial contamination of the compositions when used in concentrations that are not toxic to the ophthalmic and otic tissues. The present invention seeks to satisfy the above needs.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to certain aminobiguanides with antimicrobial activity and to pharmaceutical compositions containing one or more of these aminobiguanides to preserve the compositions without being contaminated by microorganisms. The invention also relates to the use of certain aminobiguanides to disinfect contact lenses. The aminobiguanides of the present invention have excellent antimicrobial activity, even at very low concentrations. These compounds retain excellent antimicrobial activity, even in the presence of media containing salts, such as saline solutions. The retention of the antimicrobial activity in the presence of sodium chloride and other salts is of utmost importance, since these salts are commonly present in the pharmaceutical compositions. For example, sodium chloride and other salts are frequently used to adjust the osmolality of the ophthalmic compositions, so that they are isotonic with respect to human tears. Sodium chloride and other salts may also be present in aqueous otic compositions. In addition, the compositions used to disinfect contact lenses frequently contain cleaning agents and other ingredients that may have an adverse effect on the activity of the antimicrobial agents. The ability of the aminobiguanides of the present invention to maintain a high level of antimicrobial activity, even in the presence of salts and other ingredients of the pharmaceutical compositions, is therefore an important feature of the present invention.

DESCRIPTION OF THE PREFERRED MODALITIES The aminobiguanide compounds of the present invention have the following formula: R 1 NH NH R 3 (I) R 2 - N - X - NH - C - NH - C - N - R 4 wherein: R1, R2, R3 and R4 are the same or different, and are selected from hydrogen, alkyl of (Ci to C2o), aminoalkyl of (Ci to C2o), aryl, arylalkyl of (C3 to C2o), aryloxyalkyl of ( C3 to C20) and cycloalkyl of (C3 to C2o); and X is (C2 to C2o) alkyl, optionally containing one or more substituents selected from a group consisting of (C3 to C20) cycloalkyl, aryl, aryl (C3 to C2o) aryloxyalkyl (C3 to C2) C20). In the above definitions of R1, R2, R3, R4 and the substituents of X, the alkyl groups may be saturated or unsaturated and may be in the form of straight or branched chains, and all groups except hydrogen may contain one or more heteroatoms . The compounds of the present invention also include pharmaceutically acceptable salts of the compounds of the formula (I). Preferred compounds of the formula (I) are those in which R1, R2, R3 and R4 are selected from the group consisting of hydrogen, (C1 to C2o) alkyl, (C1 to C20) aminoalkyl and (C3) cycloalkyl to C2o), and X is selected from the group consisting of (C2 to C2o) alkyl and (C2 to C20) alkyl substituted with one or more cycloalkyl groups of (C3 to C2o). The most preferred compounds are those in which R1, R2, R3 and R4 are hydrogen or (C1 to C20) alkyl, and X is (C2 to C10) alkyl or (C2 to C10) alkyl containing one or more cycloalkyl substituents of (C3 to C20). The following chart illustrates examples of these compounds: The compound wherein X is propyl, R1 is methyl, R2 is dodecyl, R3 is hydrogen and R4 is 1,4-dimethylpentyl (ie, compound number 1) is the most preferred compound of the formula (I). The compounds of the formula (I) can be synthesized according to the following reaction scheme: .2HCI Suitable methods for synthesizing the compounds of the formula (I) are also demonstrated by the following examples, which describe the synthesis of certain preferred compounds: EXAMPLE 1 Synthesis of compound number 1: .2HCI A hydrochloride mixture of 2 was reacted, 5-dimethylhexylamine (3 g, 19.9 mM) and 1.96 g (22 mM) of sodium dicyanamide in 30 ml of 1-butanol under reflux for 6 hours and concentrated in vacuo. It was suspended in 200 ml of water and extracted with chloroform (2 × 200 ml). The organic layer was washed with water, and dried over MgSO 4, and concentrated in vacuo. This residue was crystallized from ethyl acetate-p-hexane to yield 3.0 g (75% yield). NMR (CDCl 3) d 5.3 (m, 3H), 3.6 (m, 1 H), 1.6 (s, 3H), 1.6-1.4 (m, 3H), 1.3 (m, 5H), and 0.9 (d, 6) . This material was used without further purification. To a pressurized bottle was added 8.0 g (24.3 mM) of N, N-dodecylmethyl-1,3-propanediamine dihydrochloride, 6.23 g (34.4 mM) of 1,4-dimethylpentylguanidine and 1.5 ml of amyl alcohol. The bottle was sealed and heated to 150 ° C. The fusion started at 110 ° C and the reaction mixture was stirred at 150 ° C for 4 hours, after which ethanol was added to dissolve the material. This material was acidified with concentrated HCl to a pH of 0-1 and precipitated with acetone to produce a white material. This was crystallized from isopropanol-acetone to yield the desired compound as a white crystal. Elemental analysis: calculated for C25H57N6C? 3 (549.14): C, 54.68; H, 10.65; N, 15.31; Cl, 19.37 found: C, 55.06; H, 10.44; N, 15.14; Cl, 19.10. NMR (DMSO-d6): d 3.7 (m, 1 H), 3.3 (m, 4H), 3.0 (m, 2H), 2.8 (s, 3H, N-CH3), 2.1 (b, 2H), 1.8 (b, 2H), 1.5 (b, 2H), 1.3 (m, 21 H), and 0.9 (d, 6H, CH). The previous structure was confirmed by LC / MS.

EXAMPLE 2 Synthesis of compound number 2: .2HCI By following the procedure described in the synthesis of compound 1 (see example 1 above) with a mixture of 0.658 g (0.658 g, 2 mM) of N, N-dodecylmethyl-1,3-propanediamine dihydrochlorides and 0.346 g (2 mM) of n-hexylcyanoguanidine, 0.5 was obtained g (49% yield) of the desired product. Elemental analysis: calculated for C25H58N6C-13: C, 54.68; H, . 65; N, 15.31; Cl, 19.37 found :, C, 54.71; H, 10.26; N, 15.29; Cl; 19.19 NMR (DMSO-d6): d 3.4-2.9 (m, 8H), 2.7 (s, 3H, N-CH3), 1.9 (b, 2H), 1.7 (b, 2H), 1.5 (b, NHCH2CH2, 2H) , 1.3. (approximately s, 26H), and 0.9 (t, 3H, CH3).

EXAMPLE 3 Synthesis of compound number 3: .2HCI 14.3 g (0.1 M) of benzylamine hydrochloride was reacted with 8.9 g (0.1 M) of sodium dicyanamide in 100 ml of n-butanol at 150 ° C for 5 hours, and treated with 50 ml of water. The organic layer recovered was washed with 0.1 N HCl (2x50ml) and water (1x50 ml) and then concentrated in vacuo to obtain a viscous material which was taken up in ethyl acetate. This material was dried over MgSO4 and crystallized from ethyl acetate-hexane to yield 13 g (75% yield). p.f. from 95 to 100 ° C. Without further purification, this was used for the next reaction. Following the same procedure as that described in the synthesis of compound 1, with 0.987 g (3 mM of N, N-dodecylmethyl-1,3-propanediamine dihydrochlorides and 0.678 g (3.9 mmoles) of the cyanoguanidine described above, the desired compound: Elemental analysis: calculated for C25H49N6CI3: C, 55.60, H, 9.14; N, 15.56, Cl 19.69 found: C, 55.32; H, 9.25; N, 15.53; C, 19.36 NMR (DMSO-de) d 7.35 approximately s, C6H5, 5H), 4.4 (s, 2H, CH2C6H5), 3.2 (t, 2H), 3.0 (broad, 4H), 2.7 (s, 3H, N-CH3), 1.9 (m.2H), 1.6 (t, 3H), 1.3 (approximately s, 18H), and 0.9 (t, 3H, CH3-CH2).

EXAMPLE 4 Synthesis of compound number 4: .2HCI The same procedure as that described in the synthesis of compound 1 (see example 1 above) was used with 0.73 g (2.2 mM) of N, N-dodecylmethyl-1,3-propanediamnane dihydrochlorides and 0.5 g (2.2 mM) of decilcianoguanidina to produce 0.5 g (38.6%) of the desired product. Elemental analysis: calculated for C28H63N6Cl3 (590.20): C, 56.98; H, 10.76; N, 14.24; Cl, 18.02 found: C, 56.68; H, 10.62; N, 14.19; Cl, 17.85 NMR (CDCl3) d 2.9 (N-CH3), 2.3 (broad, 2H), 1.9 (broad, 2H), 1.7 (wide, 2H), 1.5 (s, 32H), and 1.1 (t, 6H) .

EXAMPLE 5 Synthesis of compound number 5: .2HCI A mixture of N, N-dodecylmethyl-1,3-propanediamine dihydrochloride (2.0 g, 6.1 mM) and 0.7 g (7.9 mM) of sodium dicyanamide was reacted in 40 ml of n-butanol under reflux for 5 hours, and aqueous NaHCO3 was added. The organic layer was separated and dissolved in a chloroform solution. This chloroform solution was washed in aqueous NaHCO3 and water, successively, and concentrated in vacuo. This residue was crystallized from methanol. p.f. from 80 to 81.

Elemental analysis calculated for C? 8H37N5 (323.53) C, 66.83; H, 11.53; N, 21.65 found: C, 66.39; H, 11.51; N, 21.71 NMR (CD3OD) d 3.2 (t, 2H), 2.4 (m, 4H), 2.2 (s, 3, N-CH3), 1.7 (m, 2H), 1.5 (m, 2H), 1.3 (s) , 18H), and 0.9 (t, 3H). This cyanoguanidine (0.5 g, 1.5 mM) was reacted with 0.51 g (1.5 mM) of N, N-dodecylmethyl-1,3-propanediamine dihydrochloride salt in 0.5 ml of amyl alcohol at 155 ° C for 3 hours and precipitated with acetone. This precipitate was dissolved in ethanol and adjusted to a pH of 1.0 with HCl. This was concentrated in vacuo and crystallized from ethanol to yield 0.71 g (70% yield). Elemental analysis: calculated for C34H73N7.4HCI (726.26): C, 56.23; H, 10.69; N, 13.56; Cl 19.53 found: C, 55.86; H, 10.30; N, 13.71; Cl, 19.20. the previous structure was confirmed by LC / MS. NMR (DMSO-dβ) d 3.3-2.9 (m, 12H), 2.7 (s, 6H, NCH3), 1.9 (b, 4H), 1.6 (b, 4H), 1.3 (s, 36H), and 0.8 (t , 6H, CH3). The compounds of the formula (I) can be used individually, in combination with one or more compounds other than the formula (I), or in combination with other disinfectants and preservatives. The compounds can be used, for example, in combination with polymeric quaternary ammonium compounds such as those described in U.S. Patent No. 4,407,791; that patent in its entirety is hereby incorporated by reference in this specification. As described in that patent with completion number '791, the polymeric quaternary ammonium compounds are useful for disinfecting contact lenses and preserving ophthalmic compositions. The most preferred polymeric quaternary ammonium compound is Polyquaternium-1. These polymeric quaternary ammonium compounds are commonly used in an amount of ab0.0001 to 0.01 weight percent / volume ("% w / v"). For the Polyquatemium-1 agent, a concentration of 0.001% w / v is preferred. The amount of each compound used will depend on the purpose of the use, for example, disinfection of contact lenses or preservation of pharmaceutical compositions, as well as the inclusion or not of other antimicrobial agents. The concentrations that are determined necessary for the aforementioned objects can be functionally described as "an effective amount for disinfecting" and "an effective amount to preserve", or variations thereof. The concentrations used to disinfect are generally in a range between 0.0001 and 0.1 percent weight / volume ("% w / v"). The concentrations used for conservation will generally be located within a range between 0.00001 and 0.01% p / v. The compositions of the present invention can be aqueous or non-aqueous, but in general they are 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), adjust the viscosity (for example, hydroxypropylmethylcellulose and other cellulose derivatives) and pH regulating agents (eg, borates, citrates, phosphates and carbonates). As indicated above, the ability of the compounds of the formula (I) to retain their antimicrobial activity in the presence of these agents is an important advantage of the present invention. The ophthalmic compositions of the present invention should be formulated so that they are compatible with the eye and / or contact lenses to be treated with those compositions. As will be appreciated by those skilled in the art, ophthalmic compositions that are applied directly to the eye will be formulated so as to have a pH and tonicity compatible with the eye. For these objects, a pH regulator will be required to maintain the pH of the composition at or near the physiological pH (ie, 7.4), as well as an agent to adjust the tonicity (eg, NaCl) so that the osmolality of the the composition is located at a level between slightly hypotonic and isotonic in relation to human tears. This range corresponds to an osmolality of between 220 and 320 milliosmoles per kilogram of water ("mOsm / kg"). The formulation of the compositions for maintaining contact lenses (eg disinfection and / or cleaning) involves similar considerations, as well as considerations regarding the physical effect of the compositions on contact lens materials and the possibility of that the components of the composition adhere or are absorbed by the lens. The contact lens disinfecting compositions of the present invention will preferably be formulated as aqueous solutions, but may also be formulated as non-aqueous solutions, as well as suspensions, gels and the like. 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 in accordance with processes known in the art. Specifically, the lenses will be removed from the eyes of patients, and subsequently they will be immersed in the compositions for a sufficient time for the lenses to be disinfected. Commonly, this immersion of the lenses in the solution lasts a whole night (that is, approximately between six and eight hours). Afterwards, the lenses will be rinsed and put back in the eye. Preferably, before immersing the lenses in the disinfectant compositions, they should also be washed and rinsed. The compositions and methods of the present invention can be used in conjunction with various types of contact lenses, including lenses generally classified as "hard" and lenses generally classified as "soft". It is also possible to include the compounds of the formula (I) in various types of pharmaceutical compositions as preservatives, to prevent microbial contamination of the compositions. Among the types of compositions which the compounds of formula (I) help to preserve are: ophthalmic pharmaceutical compositions, such as topical compositions used for the treatment of glaucoma, infections, allergies or inflammation; otic pharmaceutical compositions, such as topical compositions used in the treatment of bacterial infections or inflammation of the ear; compositions for maintaining contact lenses, such as cleaning products and products to improve the ocular comfort of patients using these contact lenses; other types of ophthalmic compositions, such as products for lubricating the eyes, artificial tears, astringents and the like; dermatological compositions, as anti-inflammatory compositions, as well as shampoos and other cosmetic compositions; and various other types of pharmaceutical compositions. The present invention is not limited to the types of pharmaceutical compositions in which the compounds of the formula (I) can be included as preservatives, but the compounds are particularly useful in preventing the ophthalmic and otic compositions from being contaminated by microbes. The compounds are particularly useful in this type of compositions due to their preservative effects even in very low concentrations, without adversely affecting the ophthalmic and otic tissues. The following examples will serve to illustrate in more detail the use of compounds of the formula (I) in pharmaceutical compositions and to demonstrate the antimicrobial activity of these compounds.

EXAMPLE 6 The following formulation represents an example of a solution for disinfecting contact lenses of the present invention. In this formulation, the aminobiguanide compounds of the present invention function to prevent the formulation from being contaminated by microbes during storage. The compounds also function as an active disinfecting agent when the formulation is applied to contact lenses.

Ingredient Concentration (% w / v) Compound 0.0005 Sorbitol 1.2 AMP-95 ™ 0.45 Sodium Citrate 0.65 Sodium Chloride 0.1 Boric Acid 0.6 Acid 0.05 Ethylenediaminetetraacetic (EDTA) Tetronic 1304 ™ 0.05 Purified Water c.b. 100 HCl / NaOH c.b.p. pH 7.8 In the above formulation, the term "compound" means any of the aminobiguanides of the formula (I). The formulation is an aqueous and isotonic solution. The solution can be prepared by successively dissolving each ingredient in water, and adjusting the pH of the resulting solution, if necessary.

EXAMPLE 7 The following formulation represents another example of a solution for disinfecting contact lenses of the present invention: Ingredient Concentration (% w / v) Compound 0.001 Boric acid 0.58 Sodium borate 0.18 Disodium EDTA 0.05 Sodium chloride 0.49 Purified water c.b. 100 NaOH / HCl c.b.p. pH 7.0 The above formulation is an aqueous and isotonic solution. It can be prepared in the same manner as the solution of example 6 above.

EXAMPLE 8 The antimicrobial activity of the example solution was evaluated 6, which contains 0.0005% w / v of the aminobiguanides identified above as compound no. 1, in relation to three key microorganisms. The evaluation was carried out to determine to what extent the solution reduced an initial population of around 106 / mL of microorganisms during a certain period of time. The results were as follows: Microorganism Reduction of Log-m Reduction of Loa after 6 hours after 24 hours Candida albicans 2.1 5.0 Serratia marcescens 3.9 6.1 Staphylococcus aureus 3.7 4.9 These results demonstrate that aminobiguanides of formula (I) have an activity powerful antimicrobial.

EXAMPLE 9 The antimicrobial activity of the solution of Example 7, which contains 0.0005% w / v of compound no. 1, using essentially the same procedure as that described in example 8 above. The results were as follows: Microorganism Reduction of Log-m Reduction of Loq-tn after 6 hours after 24 hours Candida albicans 1.4 4.0 Serratia marcescens 3.0 4.8 Staphylococcus aureus 3.4 4.6 These results corroborate the potent antimicrobial activity of the aminobiguanides of the present invention.

EXAMPLE 10 The antimicrobial activity of compound no. 1 at a concentration of 0.0005% w / v in water. The results were the following: Microorganism Log-m reduction Login reduction after 6 hours after 24 hours Candida albicans 2.1 3.8 Serratia marcescens 5.5 3.9 Staphylococcus aureus 4.1 6.0 These results show that the antimicrobial activity of the solutions evaluated in examples 8 and 9 above can be attributed to the aminobiguanides of the present invention (ie, to compound No. 1), and not to other components of the solutions. When comparing the activity of the compound no. 1 when in a distilled water vehicle, with the activity of the compound no. 1 when in regulated isotonic solutions, it can be appreciated that the aminobiguanides of the present invention retain their antimicrobial activity when used in the presence of sodium chloride and other excipients commonly present in pharmaceutical compositions. This is evident when comparing the antimicrobial activity demonstrated in Examples 8 and 9 with the antimicrobial activity demonstrated in Example 10.

Claims (19)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A sterile pharmaceutical composition for disinfecting contact lenses, including a compound of the following formula, in sufficient quantity to disinfect the lenses: R1 NH NH R3 R 22 - N i - X - NH - C ll - NH - C ll - N i- ^ R4 (l) wherein: R1, R2, R3 and R4 are the same or different and are selected from a group consisting of hydrogen, alkyl of (Ci to C2o), aminoalkyl of (Ci to C2o), aryl , arylalkyl of (C3 to C20), aryloxyalkyl of (C3 to C2o) and cycloalkyl of (C3 to C2o); and X is (C2 to C2o) alkyl, optionally containing one or more substituents selected from a group consisting of (C3 to C20) cycloalkyl, aryl, arylalkyl (C3 to C2o) and aryloxyalkyl (C3 to C2). C2o), or a pharmaceutically acceptable salt thereof; and a watery vehicle for them.
2. 2. A composition according to claim 1, further characterized in that R1, R2, R3 and R4 are selected from a group consisting of hydrogen, (C-? C2o) alkyl, benzyl and 1,4-dimethylpentyl, and X is selected from a group consisting of alkyl of (C2 to C10) and alkyl of (C2 to C10) substituted with cycloalkyl of (C3 to C2o) - 3. A composition according to claim 2, further characterized in that X is propyl, R1 is methyl, R2 is dodecyl, R3 is hydrogen, and R4 is selected from a group consisting of 1,4-dimethylpentyl, heptyl, benzyl, decyl and N-methyl-N-dodecylaminopropyl. 4. A composition according to claim 2, further characterized in that R1 is methyl, R2 is dodecyl, R3 is hydrogen, R4 is 1,4-dimethylpentyl and X is propyl. 5. A composition according to claim 1, further characterized in that the composition includes 0.001 to 0.01% w / v of a polymeric quaternary ammonium compound. 6. A composition according to claim 5, further characterized in that the polymeric quaternary ammonium compound includes Polyquatemium-1 at a concentration of 0.001% w / v. 7. A method for disinfecting contact lenses that includes applying the composition of claim 1 to the lenses for a sufficient time to disinfect these lenses. 8. A method according to claim 7, further characterized in that the lenses are immersed in the composition for at least 4 hours. 9.- A composition of the following formula: R1 NH NH R3 I I I I I? (R 2 -N-X-NH-C-NH-C-N-R 4 wherein: R 1, R 2, R 3 and R 4 are selected from a group consisting of hydrogen, alkyl (Ci to C 20), aminoalkyl of ( C1 to C20) and cycloalkyl of (C3 to C20), and X is selected from a group consisting of (C2 to C10) alkyl and (C2 to C10) alkyl substituted with (C3 to C2o) cycloalkyl; pharmaceutically acceptable salt thereof 10. A compound according to claim 9, further characterized in that R1, R2, R3 and R4 are selected from a group consisting of hydrogen and alkyl of (C1 to C2o) -11- A compound according to claim 10, further characterized in that X is propyl, R1 is methyl, R2 is dodecyl, R3 is hydrogen, and R4 is selected from a group consisting of 1,4-dimethylpentyl, heptyl, decyl and N- Methyl-N-dodecylaminopropyl 12. A compound according to claim 11, further characterized in that R1 is methyl, R2 is dodecyl, R3 is hydrogen, O, R 4 is 1,4-dimethylpentyl, and X is propyl. 13. A pharmaceutical composition that includes an effective amount of the compound of claim 9 to prevent the composition from being contaminated by microbes. 14. A pharmaceutical composition according to claim 13, further characterized in that the composition is an aqueous ophthalmic composition. 15. - A pharmaceutical composition according to claim 13, further characterized in that the composition is an aqueous otic composition. 16. A pharmaceutical composition according to claim 13, characterized further because the composition is used to maintain contact lenses. 17. A pharmaceutical composition according to claim 16, further characterized in that the composition contains a compound of the formula (I), wherein R1, R2, R3 and R4 are selected from a group consisting of hydrogen and alkyl of ( Ci to C2o), and X is selected from a group consisting of (C2 to Cio) alkyl and (C2 to C10) alkyl substituted with (C3 to C20) cycloalkyl. 18. A pharmaceutical composition according to claim 17, further characterized in that the composition contains a compound of the formula (I), wherein X is propyl, R1 is methyl, R2 is dodecyl, R3 is hydrogen, and R4 is selected of a group that consists of 1,4-dimethylpentyl, heptyl, benzyl, decyl and N-methyl-N-dodecylaminopropyl. 19. A pharmaceutical composition according to claim 18, further characterized in that the composition contains a compound of the formula (I), wherein R1 is methyl, R2 is dodecyl, R3 is hydrogen, R4 is 1,4-dimethylpentyl and X is propyl.