Use of diamines to disinfect and clean contact lenses and preserve ophthalmic compositions

N,N-dialkyl and N'-alkylethylene diamines of the formula: ##STR1## wherein R, R.sup.1 and R.sup.2 are as described in the specification. The compounds are useful in disinfecting and cleaning contact lenses and preserving ophthalmic products.

BACKGROUND OF THE INVENTION 
The present invention relates to the field of ophthalmology. More 
particularly, the invention is directed to solutions for disinfecting 
contact lenses, and to the chemical preservation of various types of 
ophthalmic products. 
Contact lenses are exposed to a broad spectrum of microbes during normal 
wear and become soiled relatively quickly. Routine cleaning and 
disinfecting of the lenses are therefore required. Although the frequency 
of cleaning and disinfecting may vary somewhat among different types of 
lenses and lens care regimens, daily cleaning and disinfecting is normally 
required. Failure to clean and disinfect the lens properly can lead to a 
multitude of problems ranging from mere discomfort when the lenses are 
being worn to serious ocular infections. Ocular infections caused by 
particularly virulent microbes, such as pseudomonas aeruginosa, can lead 
to loss of the infected eye(s) if left untreated or if allowed to reach an 
advanced stage before treatment is initiated. It is therefore extremely 
important that patients disinfect their contact lenses in accordance with 
the regimen prescribed by their optometrist or ophthalmologist. 
Unfortunately, patients frequently fail to follow the prescribed regimens. 
Many patients find regimens to be difficult to understand and/or 
complicated, and as a result do not comply with one or more aspects of the 
regimen. Other patients may have a negative experience with the regimen, 
such as ocular discomfort attributable to the disinfecting agent, and as a 
result do not routinely disinfect their lenses or otherwise stray from the 
prescribed regimen. In either case, the risk of ocular infections is 
exacerbated. 
Despite the availability of various types of contact lens disinfecting 
systems, such as heat, hydrogen peroxide, and other chemical agents, there 
continues to be a need for improved systems which: 1) are simple to use, 
2) have potent antimicrobial activity, and 3) are nontoxic (i.e., do not 
cause ocular irritation as the result of binding to the lens material). 
The present invention is directed to meeting this need. 
SUMMARY OF THE INVENTION 
The present invention is directed to certain novel N,N-dialkyl, N'-alkyl, 
ethylene diamines, and to the use of these compounds and related compounds 
to disinfect contact lenses and to preserve ophthalmic preparations. The 
invention is also directed to contact lens disinfecting compositions which 
contain one or more of the subject compounds, and to various types of 
ophthalmic compositions (e.g., pharmaceuticals, artificial tears and 
comfort drops) which contain the compounds for purposes of preserving the 
compositions against microbial contamination. 
In addition to having antimicrobial activity, including both antibacterial 
and antifungal activity, the compounds of the present invention are also 
surface active. As a result, the compounds also help to clean contact 
lenses by facilitating the removal of deposits from the lenses. 
The diamines of the present invention retain their antimicrobial activity 
in the presence of Na.sup.+, Ca.sup.++, Cl.sup.- and other inorganic ions 
produced by the dissociation of alkaline and alkaline earth metal salts 
(e.g., sodium chloride and calcium chloride), and are compatible with 
polymers and surfactants frequently used in ophthalmic products, such as 
polyvinylpyrrolidone, and polyoxyethylene/polyoxypropylene copolymers of 
ethylene diamines. In fact, it has been determined that the presence of 
sodium chloride may actually enhance the antimicrobial activity of the 
diamines of the present invention. These properties represent significant 
advantages, relative to many of the antimicrobial agents previously used 
in the ophthalmic field. 
DESCRIPTION OF PREFERRED EMBODIMENTS 
The compounds used in the present invention comprise one or more compounds 
of the following formula, or pharmaceutically acceptable salts thereof 
(e.g., hydrohalide salts): 
##STR2## 
wherein: R is C.sub.6 -C.sub.18 saturated or unsaturated alkyl, alkylaryl, 
or alkoxyaryl; 
R.sup.1 is hydrogen, or C.sub.1 -C.sub.18 saturated or unsaturated alkyl, 
alkylaryl, alkoxyaryl, or alkanol; 
n is 2 to 16, preferably 2 to 4; and 
R.sup.2 is C.sub.1 -C.sub.8 saturated or unsaturated alkyl or alkanol. The 
compounds wherein R.sup.2 is ethyl are particularly preferred, as are the 
following compounds: 
______________________________________ 
Compound No. 
R R.sup.1 n R.sup.2 
______________________________________ 
1 Dodecyl H 2 Ethyl 
2 Tetradecyl 
H 2 Ethyl 
3 Hexadecyl H 2 Ethyl 
4 Oleyl H 2 Ethyl 
5 Stearyl H 2 Ethyl 
6 Dodecyl H 3 Methyl 
7 Tetradecyl 
H 3 Methyl 
8 Hexadecyl H 3 Methyl 
9 Oleyl H 3 Methyl 
10 Stearyl H 3 Methyl 
11 Oleyl H 2 CH.sub.2 CH.sub.2 OH 
12 Oleyl H 3 CH.sub.2 CH.sub.2 OH 
13 Oleyl CH.sub.2 CH.sub.2 OH 
2 CH.sub.2 CH.sub.2 OH 
14 Oleyl CH.sub.2 CH.sub.2 OH 
3 CH.sub.2 CH.sub.2 OH 
______________________________________ 
The most preferred compound is N,N-diethyl-N'-oleyl ethylene diamine (i.e., 
Compound No. 4), which has the following general formula: 
EQU CH.sub.3 (CH.sub.2).sub.6 CH.sub.2 CH=CHCH.sub.2 (CH.sub.2 ).sub.6 CH.sub.2 
NHCH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.3).sub.2 
The compounds of the present invention can be synthesized in accordance 
with the following reaction scheme: 
1. oleic acid.fwdarw.oleoyl chloride 
2. oleoylchloride+NH.sub.2 CH.sub.2 CH.sub.2 N(C.sub.2 H.sub.5).sub.2 
.fwdarw.oleoyl-NHCH.sub.2 CH.sub.2 N(C.sub.2 H.sub.5).sub.2 
3. oleoyl-NHCH.sub.2 CH.sub.2 N(C.sub.2 H.sub.5).sub.2 
.fwdarw.Oleyl-NHCH.sub.2 CH.sub.2 N(C.sub.2 H.sub.5).sub.2 
The starting materials for the synthesis of the target compounds are 
readily available commercially (e.g., from Aldrich Chemical Company, 
Milwaukee, Wis.). The corresponding acid halide is reacted with the 
corresponding amine to provide the amide. The amide is reduced with 
lithium aluminum hydride to the desired amine. The purification is 
performed either by high vacuum distillation or by column chromatography 
(with silica gel as a support). These compounds are characterized by gas 
chromatography, infrared, nuclear magnetic resonance spectra, and 
elemental analysis. 
The compounds of formula (I) wherein R.sub.2 is methyl or hydroxyethyl are 
known. Such compounds are described in the following articles: Bass, et 
al., Journal of Dental Research, volume 54, number 5, pages 972-977 
(1975); and Powers, et al., Journal of Pharmaceutical Sciences, volume 64, 
number 5, pages 883-885 (1975). The entire contents of both of these 
articles are hereby incorporated in the present specification by 
reference. The above-cited articles do not describe the use of compounds 
of formula (I) as disinfectants or preservatives in ophthalmic products, 
particularly products used in the care of contact lenses. 
The compounds of formula (I) can be used individually, in combination with 
one or more other compounds of formula (I), or in combination with other 
disinfectants or preservatives. The compounds may, for example, be used in 
combination with the polymeric quaternary ammonium compounds described in 
U.S. Pat. No. 4,407,791; the entire contents of that patent are hereby 
incorporated in the present specification by reference. As described in 
the '791 patent, those polymeric quaternary ammonium compounds are useful 
in disinfecting contact lenses and preserving ophthalmic compositions. 
The amount of each compound used will depend on the purpose of the use, 
e.g., disinfection of contact lenses or preservation of ophthalmic 
products, and the absence or inclusion of other antimicrobial agents. The 
concentrations determined to be necessary for the above-stated purposes 
can be functionally described as "an amount effective to disinfect" and 
"an amount effective to preserve" or variations thereof. The 
concentrations used for disinfection will generally be in the range of 
from about 0.0001 to about 0.1 percent by weight based on the total weight 
of the composition ("wt. %"). The concentrations used for preservation 
will generally be in the range of from about 0.00001 to about 0.01 wt. %. 
The compounds of formula (I) may be included in various types of ophthalmic 
compositions as preservatives, so as to prevent microbial contamination of 
the compositions. The types of compositions which may be preserved by the 
compounds of formula (I) include: ophthalmic pharmaceutical compositions, 
such as topical compositions used in the treatment of glaucoma, 
infections, allergies or inflammation; compositions for treating contact 
lenses, such as cleaning products and products for enhancing the ocular 
comfort of patients wearing contact lenses; ana various other types of 
compositions, such as ocular lubricating products, artificial tears, 
astringents, and so on. The compositions may be aqueous or nonaqueous, 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., 
polyvinyl pyrrolidone and polyoxyethylene/polyoxypropylene copolymers), 
viscosity adjusting agents (e.g., hydroxypropyl methyl cellulose and other 
cellulose derivatives) and buffering agents (e.g., borates, citrates, 
phosphates and carbonates). The present invention is not limited with 
respect to the types of ophthalmic compositions in which the compounds of 
formula (I) may be contained as preservatives. In fact, as already noted 
above, the compatibility of the compounds of formula (I) with other 
ingredients of ophthalmic compositions, such as inorganic ions, polymers 
and surfactants, is a distinct advantage of the present invention, 
relative to antimicrobial agents previously utilized in the ophthalmic 
field. 
As with the ophthalmic compositions of the present invention which contain 
one or more compounds of formula (I) as preservatives, the form of the 
compositions of the present invention containing one or more of the 
compounds for purposes of disinfecting contact lenses is not limited. The 
contact lens disinfecting compositions of the present invention will 
preferably be formulated as aqueous solutions, but may also be formulated 
as nonaqueous solutions, as well as suspensions, gels, and so on. The 
compositions may contain a variety of tonicity agents, surfactants, 
viscosity adjusting agents and buffering agents, as described above. The 
chemical compatibility of the compounds of formula (I) is also a 
significant advantage with respect to the use of these compounds in the 
contact lens disinfecting compositions of the present invention. 
The above-described compositions may be used to disinfect contact lenses in 
accordance with processes known to those skilled in the art. More 
specifically, the lenses will first be removed from the eyes of the 
patients, and then will be immersed in the compositions for a time 
sufficient to disinfect the lenses. This immersion will typically be 
accomplished by means of soaking the lenses in a solution overnight (i.e., 
approximately six to eight hours). The lenses will then be rinsed and 
placed in the eye. Prior to immersion in the disinfecting compositions, 
the lenses will preferably also be cleaned and rinsed. 
The compounds of formula (I) also have surface active properties. As a 
result of these properties, the compounds are also useful in cleaning 
contact lenses. More specifically, the surfactant properties of the 
compounds facilitate the removal of deposits typically accumulated on 
contact lenses when worn by human patients. These deposits vary from 
patient to patient, but will typically include proteins, lipids, 
polysaccharides and mixtures thereof, as well as various other soils which 
may accumulate on the lenses during normal wear and handling. The 
compounds will exhibit some cleaning effect even at the relatively low 
concentrations required for purposes of preserving ophthalmic compositions 
or disinfecting contact lenses. This cleaning effect is therefore useful 
as a supplement to the effect of other cleaning agents which may be 
contained in the compositions, such as anionic or nonionic surfactants. 
Moreover, when used at a concentration of 0.01 wt. % or higher, the 
compounds exhibit a more pronounced cleaning effect. The manner in which 
the cleaning effect of the compounds of formula (I) is utilized will 
depend on the type of contact lens being treated, the severity and type of 
the deposits on the lenses, and the overall treatment regimen used by the 
patient. The selection of other components for inclusion in the contact 
lens cleaning compositions of the present invention will also depend on 
these factors. The cleaning compositions will generally contain one or 
more of the compounds of formula (I) in an amount of at least 0.01 wt. %, 
and preferably from about C.01 to 1.0 wt. %. 
The above-described compositions may be used to clean contact lenses in 
accordance with known processes. For example, the lenses, after first 
being removed from the eye and preferably also rinsed, may be lightly 
rubbed with a small amount of the compositions between the fingers, or may 
be immersed in a somewhat larger volume of the compositions and then 
allowed to soak. The lenses are then rinsed and disinfected before being 
replaced in the eyes of the patients. 
All of the above-described compositions will be formulated so as to be 
compatible with the eye and/or contact lenses to be treated with the 
compositions. As will be appreciated by those skilled in the art, the 
ophthalmic compositions intended for direct application to the eye will be 
formulated so as to have a pH and tonicity which are compatible with the 
eye. This will normally require a buffer to maintain the pH of the 
composition at or near physiologic pH (i.e., 7.4) and may require a 
tonicity agent to bring the osmolality of the composition to a level at or 
near 300-320 milliosmoles. The formulation of compositions for 
disinfecting and/or cleaning contact lenses will involve similar 
considerations, as well as considerations relating to the physical effect 
of the compositions on contact lens materials and the potential for 
binding or absorption of the components of the composition by the lens. 
The compositions and methods of the present invention may be used in 
conjunction with various types of contact lenses, including both lenses 
generally classified as "hard" and lenses generally classified as "soft".

The following examples are presented to further illustrate methods of 
synthesizing the novel diamines of the present invention: 
EXAMPLE 1 
N,N-diethyl-N'-octylethylenediamine 
A mixture of N,N-diethylethylenediamine (9.6 g, 0.0826 mol) and 8.4 g 
(0.0826 mol) of triethylamine in 40 ml of chloroform was added dropwise to 
the ice cold chloroform solution (40 ml) of octanoyl chloride (13.4 g, 
0.0826 mol). After addition, the ice bath was removed and the solution was 
stirred for 5 hours at room temperature. The reaction mixture was stirred 
with aqueous sodium bicarbonate for one hour. The organic layer was then 
dried over magnesium sulfate leaving a yellow liquid which was 
concentrated in vacuo. The yellow liquid was subject to high vacuum 
distillation to yield 9.65 g (0.040 mol, 48.3%, b.p..sub.0.05mm 
=115.degree. C.). The above amide (9.65 g, 0.040 mol) was reduced with 
lithium aluminum hydride (1.7 g, 0.045 mol) to yield 6.94 g (0.030 mol, 
76.1%) of the product after vacuum distillation: (b.p..sub.0.05mm 
=77.degree. C.). NMR (CDCl.sub.3) .delta. 2.7-2.4 (m, 10H, NCH.sub.2 and 
NHCH.sub.2), 1.6 (s, 1H, NH), 1.5 (m, 2H, NHCH.sub.2 CH.sub.2), 1.28 (s, 
10H, NHCH.sub.2 CH.sub.2 (CH.sub.2).sub.5), 1.01 (t, 6H, NCH.sub.2 
CH.sub.3), 0.88 (t, 3H, CH.sub.3). Elemental Analysis: Caled. for C.sub.14 
H.sub.32 N.sub.2 (228.41): C, 73.61; H, 14.12; N, 12.26. Found: C, 73.68; 
H, 14.76; N, 12.12. 
EXAMPLE 2 
N-n-dodecyl-N'N'-diethylethylenediamine 
5.12 g (23.4 mmol) of lauroyl chloride and 3.41 g (29.3 mmol) of 
N,N-diethylethylenediamine were reacted in dry chloroform. The reaction 
mixture was concentrated by evaporation of chloroform and treated with 
sodium bicarbonate in a mixture of ethanol and water. Following extraction 
with chloroform, the combined chloroform extracts were dried and 
concentrated, upon which the amide began to crystallize. Without further 
purification, the amide was reduced with lithium aluminum hydride in THF 
using standard procedures. After quenching and filtration of the reaction 
mixture, the filtrate was dried and concentrated then distilled under 
reduced pressure to yield 2.29 g (34%) of the diamine (bp 115-119.degree., 
20 v). Purity by GC&gt;99%. 
.sup.1 H NMR (CDCl.sub.3, 200 MHz) .delta. 2.68-2.40 (m, 10H,--CH.sub.2 
NHCH.sub.2 CH.sub.2 N(CH.sub.2 CH.sub.2).sub.2), 1.45 (m, 2H, --CH.sub.2 
CH.sub.2 CH.sub.2 NH), 1.25 (s, 18H, CH.sub.3 (CH.sub.2).sub.9 --), 1.10 
(t, 6H, N(CH.sub.2 CH.sub.3).sub.2), 0.85 (t, 3H, CH.sub.3). 
EXAMPLE 3 
N-Tetradecyl-N',N',-diethylethylenediamine 
A mixture of N,N-diethylethylenediamine (5.8 g. 0.05 mole) and 
triethylamine (5 g.) in 250 ml of chloroform was cooled on ice bath and 
reacted with 12.3 g (0.05 mol) of myristoyl chloride by adding dropwise. 
The reaction temperature was maintained below 10.degree. C. After the 
completion of the addition, the ice bath was removed and the reaction 
mixture was refluxed for two hours. The reaction mixture was stirred with 
NaHCO.sub.3 at room temperature for one hr. and the chloroform layer was 
washed with NaHCO.sub.3 saturated solution and dried with MgSO.sub.4. The 
concentration in vacuo yielded a crystalline material of 14 g. (86%). Nmr 
spectra, IR, and GC confirmed the structure of the above compound. 
This amide (10 g, 0.03 mol) was reduced with lithium aluminum hydride (1.2 
g.) in 200 ml of tetrahydrofuran solvent to yield 8 g. (84%) of the 
diamine after high vacuum distillation (b.p..sub.0.01 =135-140.degree. 
C.). Nmr (CDCl.sub.3) 2.7-2.45 (m, 10, N--CH.sub.2), 1.7 (br, 1, NH), 1.5 
(m, 2, N--CH.sub.2 CH.sub.2), 1.3 (app. s, 22, CH.sub.2), 1.0 (t, 6, 
NCH.sub.2 CH.sub.2), and 0.9 (t, 3, CH.sub.3). Elemental Analysis: Calcd. 
for C20H44N2 (312.58): C, 76.85; H, 14.19; N, 8.96 Found: C, 76.78; H, 
14.37; N, 8.96. 
EXAMPLE 4 
N,N-diethyl-N'-oleylethylenediamine 
11.37 g (30.0 mmol) of N,N-diethyl-N'-oleoylethylenediamine was reduced 
with lithium aluminum hydride in THF using standard procedures. After 
quenching and filtration of the reaction mixture, the filtrate was dried 
and concentrated then redissolved in ethanol and acidified with HCl. The 
salt was recrystallized twice from ethyl acetate, affording 9.84 g (75%) 
of the diamine. Purity by GC, 92.5%. Anal. calcd. for C.sub.24 H.sub.52 
Cl.sub.2 N.sub.2 : C, 65.58; H, 1192: N, 6.37. Found: C, 65.50; H, 11.75; 
N, 6.35. 
.sup.1 H NMR (CDCl.sub.3, 200 MHz) .delta. 5.34 (t, 2H, CH.dbd.), 3.92 (q, 
2H, NCCH.sub.2 CH.sub.2 --N), 3.46 (t, 2H, NHCH.sub.2 CH.sub.2 --N), 3.27 
(q, 4H, N(CH.sub.2 CH.sub.3).sub.2), 3.00 (q, 2H, --CH.sub.2 CH.sub.2 
CH.sub.2 --N), 2.10 (q, 4H, CH.sub.2 CH.dbd.), 1.85 (m, 2H, --CH.sub.2 
CH.sub.2 CH.sub.2 --N), 1.50 (t, 6H, N(CH.sub.2 CH.sub.3), 1.27 (s, 22H, 
--CH.sub.2 --), 0.88 (t, 3H, CH.sub.3). 
EXAMPLE 5 
N-(3,5-di-t-butylbenzyl)-N',N'-diethylethylenediamine 
This compound was prepared by chlorination of 3,5-di-t-butylbenzoic acid 
with thionyl chloride using standard procedures to give 
3,5-di-t-butylbenzoyl chloride. 3.26 g (12.9 mmol) of the chloride was 
then reacted with 1.95 g (16.8 mmol) of N,N-diethylethylenediamine in dry 
chloroform. The reaction mixture was concentrated by evaporation of 
chloroform and treated with sodium bicarbonate in a mixture of ethanol and 
water. Following extraction with chloroform, the combined chloroform 
extracts were dried and concentrated, upon which the amide began to 
crystallize. Without further purification, the amide was reduced with 
lithium aluminum hydride in THF using standard procedures. After quenching 
and filtration of the reaction mixture, the filtrate was dried and 
concentrated then distilled under reduced pressure to yield 2.00 g (49%) 
of the diamine.(bp 105-108.degree., 10 v). Purity by GC&gt;99%. 
.sup.1 H NMR (CDCl.sub.3, 200 MHz) .delta. 7.30-7.15 (2 s, 3H, --C.sub.6 
H.sub.3 --), 3.79 (s, 2H, C.sub.6 --CH.sub.2 --), 2.70 (t, 2H, NHCH.sub.2 
CH.sub.2 --N), 2.50 (q, 4H, N(CH.sub.2 CH.sub.3).sub.2), 1.32 (s, 18H, 
--C(CH.sub.3).sub.3), 1.00 (t, 6H, CH.sub.3). 
The following examples are presented to further illustrate ophthalmic 
compositions which may contain one or more of the compounds of formula 
(I): 
EXAMPLE 6 
The following formulation might serve as a vehicle for an ophthalmic drug. 
The formulation would contain one or more compounds of formula (I) as a 
preservative. 
______________________________________ 
Ingredient Amount (wt. %) 
______________________________________ 
Sodium Chloride 0.5% 
Mannitol 2.5% 
HEPES 0.119% 
NaOH/HCl pH 7.0 
Purified water QS 100 
______________________________________ 
EXAMPLE 7 
The following formulation may be utilized as a contact lens disinfecting 
solution. The formulation would contain one or more compounds of formula 
(I) as a disinfectant. 
______________________________________ 
Ingredient Amount (wt. %) 
______________________________________ 
Mannitol 0.64% (w/v) 
Boric Acid 0.225% 
Sodium Borate 0.08% 
Sodium Citrate 0.46% 
Citric Acid 0.016% 
Sodium Chloride 0.48% 
Disodium Edetate 0.05% 
NaOH/HCl pH 7.0 
Purified Water QS 100 
______________________________________ 
EXAMPLE 8 
The following formulation may be utilized as a contact lens disinfecting 
solution, and would also aid in the cleaning of the lens. 
______________________________________ 
Ingredient Amount (wt. %) 
______________________________________ 
Compound No. 4 0.01% 
Boric Acid 0.58% 
Sodium Borate 0.18% 
Sodium Chloride 0.49% 
Disodium Edetate 0.05% 
Polaxomine 0.1% 
NaOH/HCl pH 7.0 
Purified Water QS 100% 
______________________________________