Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1999-01-05
2001-11-13
Killos, Paul J. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C560S067000
Reexamination Certificate
active
06316500
ABSTRACT:
BACKGROUND OF THE INVENTION
Various species of p-hydroxy benzoic acid esters and their salts have found use as preservatives for foods and beverages as is disclosed in U.S. Pat. Nos. 2,046,324; 2,056,176; 3,767,827; 4,366,171 and 4,568,382. Although some of these esters possess preservative properties over a broad spectrum of fungicides, they exhibit low solubility in water which limits their use. Other hydroxy benzoates are effective only against gram positive microorganisms and several of these esters produce residues which are harmful to humans or the environment; accordingly their continued use has been barred.
The foregoing drawbacks limit the selection of totally acceptable and effective fungicidal agents. Moreover, it has been found that closely related compounds exhibit quite different control abilities and microorganism selectivity. For example, heptyl p-hydroxybenzoate has been used at about 10 ppm as a beer preservative to kill saprogenous microorganisms; however it has limited solubility in beer so that the beer becomes turbid at about 0° C. Similar drawbacks are noted for the treatment of soy and other beverages.
To be commercially acceptable, the type of hydroxy benzoate must be moderately water soluble and leave no toxic residue, they should exhibit high activity at low concentrations against a broad spectrum of microorganisms and fungi and they must be economical to prepare and apply. Accordingly it is an object of this invention to achieve these aims in a hydroxy benzoate derivative which is modified so as to balance significantly improved water solubility with high anti microorganism and fungicidal activity against both gram positive and gram negative species. Another object of the invention is to provide non-toxic hydroxy benzoates by an economical and commercially feasible process. These and many other benefits of the invention will become apparent from the following description and disclosure.
THE INVENTION
In accordance with this invention there is provided new and useful hydroxy benzoates defined by the formula:
wherein Y is hydrogen, hydroxy, halo, a C
1
to C
6
alkyl or a C2 to C
6
alkyl ether;
R is a C
4
to C
6
mono- or di-olefinically unsaturated hydrocarbon radical, a C
4
to C
7
mono- or di-acetylenically unsaturated hydrocarbon radical or a C
2
to C
3
acetylenically unsaturated hydrocarbon radical when one or both of X and Y is other than hydrogen and
X is hydrogen, hydroxy, halo, a C
1
to C
6
alkyl, a C
2
to C
6
alkyl ether or
in which A is selected from the group of X,
B is selected from the group of Y and
R
1
is hydrogen, hydroxy, C
1
to C
6
alkyl, C
1
to C
6
alkoxy or —COOR
2
in which R
2
is C
1
to C
6
alkyl, a C
2
to C
6
olefinically unsaturated hydrocarbon radical or a C
2
to C
7
acetylenically unsaturated hydrocarbon radical.
Also in accordance with this invention there is provided food, beverage and cosmetic compositions containing an effective preservative amount of a hydroxy benzoates having the above formula except for substituent R, which in the case of the preservative composition for the above substances, can be a C
2
to C
6
olefinically unsaturated hydrocarbon radical or a C
2
to C
6
acetylenically unsaturated hydrocarbon radical.
The present hydroxy benzoates exhibit good anti-microbial and fungicidal activity for a broad spectrum of gram negative and gram positive substances which cause deterioration of beverage, food, drug and cosmetic products, including alcoholic and non-alcoholic beverages, such as beer, ale, wines, fruit juices, milk, etc., frozen and canned meat, vegetable and fruit food products, bread and pastries, shampoo, face and body lotions, hair rinses and conditioners, bath oils and the like. The present hydroxy benzoate preservative is preferably incorporated with such food, beverage, topically applied drug or cosmetic products in a concentration of between about 0.1 and about 1.5 wt. %, most preferably between about 0.2 and about 1 wt. %. In foods and beverages, less that 1 wt. % of the hydroxy benzoate is highly effective and can be incorporated as a water or aqueous solution.
The present hydroxy benzoates achieve significantly improved water solubility and high anti-microbial and fungicidal activity which is achieved by a controlled lipophilic/hydrophilic balance between the substituents on the aromatic ring. The activity of the present compounds extends over a broad spectrum to include control of both gram negative and gram positive microorganisms and fungi including
A. niger, B. cepacia, C. albicans, E. coli, P. aeruginosa, S. aureus, stephylococcus, salmonella, P. eugaris, S corepislac
, myxo- and eu-mycotina and other mycota and organisms affecting comestable and cosmetic products.
Particularly preferred among instant hydroxy benzoates are the propargyl dihydroxy benzoate, propargyl chloro hydroxy benzoate, 2,4-hexadienyl-4-hydroxy benzoate, 2,4-hexadienyl-2,4-dihydroxy benzoate, 1, 3-butadienyl-2,4-dihydroxy benzoate, 1,3-butadienyl-3-chloro-2,4-dihydroxy benzoate, 3-butynyl-2,4-dihydroxy benzoate, and 3-butynyl-4-hydroxy benzoate.
In each of the above benzoates, the lipophilic R group is selected to balance the remaining hydrophilic ring substituents, such as —OH, alkoxy, halo etc. It is now discovered that the activity of the preservative varies directly with the length of the hydrocarbon chain up to 6 carbon atoms in the R of the ester linkage; whereas the water solubility decreases and must be modified by selection of the hydrophilic ring substituents.
The hydroxy benzoates of this invention can be prepared by contacting reactant the hydroxy benzoic acid
in the presence of an alkali metal hydroxide with a coreactant which is the halide of the R group in the above benzoate formula and in the presence of a condensing agent, e.g. dicyclohexylcarbamide, in a 1:1-1:1.5 benzoate to agent mole ratio. The reaction is carried out in at least 40 wt. % solution containing a suitable solvent such as an alcohol, e.g. isopropanol, an ether, dioxane, tetrahydrofuran, acetone, methylene chloride and the like.
Alternatively the benzoate can be prepared by reaction of the above hydroxy benzoic acid with the aliphatic alcohol coreactant corresponding to the R group in the above formula and in the presence of a condensing agent in a 1:1-1:1.5 benzoate to agent mole ratio. This reaction is also carried out in at least a 40 wt. % solution of a suitable solvent of the above group, excluding alcohol.
The mole ratio of reactant to coreactant in the above processes is generally between about 1:1 and about 2.5:1, preferably between about 1:1 and 1.5:1 and the esterification reaction is carried out under constant agitation and at reflux temperature, e.g. between about 400 and about 100° C., preferably between about 500 and about 70° C. over a period of from 2 to 24 hours, more often from 4 to 12 hours. The resulting solid reaction hydroxy benzoate product is then distilled or evaporated to remove solvent, extracted with for example methylene chloride followed by water washing and then dried.
The hydroxybenzoates of this invention exhibit good water solubility and preservative properties for foods, beverages, cosmetics, soaps, creams and lotions and other formulations, e.g. agrichemical and pharmaceutical formulations.
The hydroxybenzoates having the formula
wherein X′ is selected from the group of X; Y′ is selected from the group of Y and R
4
is a C
2
to C
6
mono- or di-olefinically unsaturated hydrocarbon radical or a C
2
to C
7
mono- or di-acetylenically unsaturated hydrocarbon radical; exhibit good water solubility and preservative properties for foods and beverages, cosmetic hair and skin care products such as, soaps, creams and lotions, pharmaceutical and agrichemical formulations including pesticides and fungicides as well as livestock pesticidal washes or dips.
When employed as a preservative, effective concentrations of the hydroxy benzoates of formula II in the above mixtures can vary from as little as about 0.001 up to about 2.0%. The hydroxybenzoates in the above
Elder Todd
Merianos John J.
Davis William J.
ISP Investments Inc.
Katz Walter
Killos Paul J.
Maue Marilyn J.
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